Piperizinones as modulators of chemokine receptor activity

ABSTRACT

The present application describes modulators of CCR3 of formula (I): 
                 
 
or pharmaceutically acceptable salt forms thereof, useful for the prevention of asthma and other allergic diseases.

FIELD OF THE INVENTION

This invention relates generally to modulators of chemokine receptoractivity, pharmaceutical compositions containing the same, and methodsof using the same as agents for treatment and prevention of inflammatorydiseases such as asthma and allergic diseases, as well as autoimmunepathologies such as rheumatoid arthritis and atherosclerosis.

BACKGROUND OF THE INVENTION

Chemokines are chemotactic cytokines, of molecular weight 6-15 kDa, thatare released by a wide variety of cells to attract and activate, amongother cell types, macrophages, T and B lymphocytes, eosinophils,basophils and neutrophils (reviewed in Luster, New Eng. J. Med., 338,436-445 (1998) and Rollins, Blood, 90, 909-928 (1997)). There are twomajor classes of chemokines, CXC and CC, depending on whether the firsttwo cysteines in the amino acid sequence are separated by a single aminoacid (CXC) or are adjacent (CC). The CXC chemokines, such asinterleukin-8 (IL-8), neutrophil-activating protein-2 (NAP-2) andmelanoma growth stimulatory activity protein (MGSA) are chemotacticprimarily for neutrophils and T lymphocytes, whereas the CC chemokines,such as RANTES, MIP-1α, MIP-1β, the monocyte chemotactic proteins(MCP-1, MCP-2, MCP-3, MCP-4, and MCP-5) and the eotaxins (-1,-2, and -3)are chemotactic for, among other cell types, macrophages, T lymphocytes,eosinophils, dendritic cells, and basophils. There also exist thechemokines lymphotactin-1, lymphotactin-2 (both C chemokines), andfractalkine (a CXXXC chemokine) that do not fall into either of themajor chemokine subfamilies.

The chemokines bind to specific cell-surface receptors belonging to thefamily of G-protein-coupled seven-transmembrane-domain proteins(reviewed in Horuk, Trends Pharm. Sci., 15, 159-165 (1994)) which aretermed “chemokine receptors.” On binding their cognate ligands,chemokine receptors transduce an intracellular signal through theassociated trimeric G proteins, resulting in, among other responses, arapid increase in intracellular calcium concentration, changes in cellshape, increased expression of cellular adhesion molecules,degranulation, and promotion of cell migration. There are at least tenhuman chemokine receptors that bind or respond to CC chemokines with thefollowing characteristic patterns: CCR-1 (or “CKR-1” or “CC-CKR-1”)[MIP-1α, MCP-3, MCP-4, RANTES] (Ben-Barruch, et al., Cell, 72, 415-425(1993), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-2A andCCR-2B (or “CKR-2A”/“CKR-2B” or “CC-CKR-2A”/“CC-CKR-2B”) [MCP-1, MCP-2,MCP-3, MCP-4, MCP-5] (Charo et al., Proc. Natl. Acad. Sci. USA, 91,2752-2756 (1994), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-3(or “CKR-3” or “CC-CKR-3”) [eotaxin-1, eotaxin-2, RANTES, MCP-3, MCP-4](Combadiere, et al., J. Biol. Chem., 270, 16491-16494 (1995), Luster,New Eng. J. Med., 338, 436-445 (1998)); CCR-4 (or “CKR-4” or “CC-CKR-4”)[TARC, MIP-1α, RANTES, MCP-1] (Power et al., J. Biol. Chem., 270,19495-19500 (1995), Luster, New Eng. J. Med., 338, 436-445 (1998));CCR-5 (or “CKR-5” OR “CC-CKR-5”) [MIP-1α, RANTES, MIP-1β] (Sanson, etal., Biochemistry, 35, 3362-3367 (1996)); CCR-6 (or “CKR-6” or“CC-CKR-6”) [LARC] (Baba et al., J. Biol. Chem., 272, 14893-14898(1997)); CCR-7 (or “CKR-7” or “CC-CKR-7”) [ELC] (Yoshie et al., J.Leukoc. Biol. 62, 634-644 (1997)); CCR-8 (or “CKR-8” or “CC-CKR-8”)[I-309, TARC, MIP-1P] (Napolitano et al., J. Immunol., 157, 2759-2763(1996), Bernardini et al., Eur. J. Immunol., 28, 582-588 (1998)); andCCR-10 (or “CKR-10” or “CC-CKR-10”) [MCP-1, MCP-3] (Bonini et al, DNAand Cell Biol., 16, 1249-1256 (1997)).

In addition to the mammalian chemokine receptors, mammaliancytomegaloviruses, herpesviruses and poxyiruses have been shown toexpress, in infected cells, proteins with the binding properties ofchemokine receptors (reviewed by Wells and Schwartz, Curr. Opin.Biotech., 8, 741-748 (1997)). Human CC chemokines, such as RANTES andMCP-3, can cause rapid mobilization of calcium via these virally encodedreceptors. Receptor expression may be permissive for infection byallowing for the subversion of normal immune system surveillance andresponse to infection. Additionally, human chemokine receptors, such asCXCR⁴, CCR², CCR³, CCR⁵ and CCR⁸, can act as co-receptors for theinfection of mammalian cells by microbes as with, for example, the humanimmunodeficiency viruses (HIV).

Chemokine receptors have been implicated as being important mediators ofinflammatory, infectious, and immunoregulatory disorders and diseases,including asthma and allergic diseases, as well as autoimmunepathologies such as rheumatoid arthritis and atherosclerosis. Forexample, the chemokine receptor CCR-3 plays a pivotal role in attractingeosinophils to sites of allergic inflammation and in subsequentlyactivating these cells. The chemokine ligands for CCR-3 induce a rapidincrease in intracellular calcium concentration, increased expression ofcellular adhesion molecules, cellular degranulation, and the promotionof eosinophil migration. Accordingly, agents which modulate chemokinereceptors would be useful in such disorders and diseases. In addition,agents which modulate chemokine receptors would also be useful ininfectious diseases such as by blocking infection of CCR³ expressingcells by HIV or in preventing the manipulation of immune cellularresponses by viruses such as cytomegaloviruses.

A substantial body of art has accumulated over the past several decadeswith respect to substituted piperidines, piperizinones and pyrrolidines.These compounds have implicated in the treatment of a variety ofdisorders.

WO 98/25604 describes spiro-substituted azacycles which are useful asmodulators of chemokine receptors:

wherein R₁ is C₁₋₆ alkyl, optionally substituted with functional groupssuch as —NR⁶CONHR⁷, wherein R⁶ and R⁷ may be phenyl further substitutedwith hydroxy, alkyl, cyano, halo and haloalkyl. Such spiro compounds arenot considered part of the present invention.

WO 95/13069 is directed to certain piperidine, pyrrolidine, andhexahydro-1H-azepine compounds of general formula:

wherein A may be substituted alkyl or Z-substituted alkyl, withZ=NR_(6a) or O. Compounds of this type are claimed to promote therelease of growth hormone in humans and animals.

WO 93/06108 discloses pyrrolobenzoxazine derivatives as5-hydroxytryptamine (5-HT) agonists and antagonists:

wherein A is lower alkylene and R⁴ may be phenyl optionally substitutedwith halogen.

U.S. Pat. No. 5,668,151 discloses Neuropeptide Y (NPY) antagonistscomprising 1,4-dihydropyridines with a piperidinyl ortetrahydropyridinyl-containing moiety attached to the 3-position of the4-phenyl ring:

wherein B may be NH, NR¹, O, or a bond, and R⁷ may be substitutedphenyl, benzyl, phenethyl and the like.

Patent publication EP 0 903 349 A2 discloses CCR-3 receptor antagonistscomprising cyclic amines of the following structure:

wherein T and U may be both nitrogen or one of T and U is nitrogen andthe other is carbon and E may be —NR⁶CONR⁵— and others.

WO 97/27752 discloses compounds of the general formula:

wherein W may be a pyrazole ring. These compounds are claimed to treatcancer as inhibitors of farnesyl-protein transferase.

WO 99/04794 is directed towards modulators of chemokine activity havingthe general formula:

wherein the claimed compounds are exclusively para-substitutedpiperidines.

WO 94/22846 discloses compounds having the general formula:

and optionally having the R¹⁰¹ and R¹⁰² connected to form a heterocyclering. These compounds are disclosed as agents for sensitizing tumorcells or as anti cancer agents.

These reference compounds are readily distinguished structurally byeither the nature of the urea functionality, the attachment chain, orthe possible substitution of the present invention. The prior art doesnot disclose nor suggest the unique combination of structural fragmentswhich embody these novel piperizinones as having activity toward thechemokine receptors.

SUMMARY OF THE INVENTION

Accordingly, one aspect of the present invention is to provide novelagonists or antagonists of CCR-3, or pharmaceutically acceptable saltsor prodrugs thereof.

The present invention also provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and a therapeuticallyeffective amount of at least one of the compounds of the presentinvention or a pharmaceutically acceptable salt or prodrug form thereof.

The present invention provides a method for treating inflammatorydiseases and allergic disorders comprising administering to a host inneed of such treatment a therapeutically effective amount of at leastone of the compounds of the present invention or a pharmaceuticallyacceptable salt or prodrug form thereof.

The present invention provides novel piperizinones for use in therapy.

The present invention provides the use of novel piperizinones for themanufacture of a medicament for the treatment of allergic disorders.

These and other features, which will become apparent during thefollowing detailed description, have been achieved by the inventors'discovery that compounds of formula (I):

or stereoisomers or pharmaceutically acceptable salts thereof, whereinB, D, E, Z, R¹, R², R³, R⁴, and R¹⁹ are defined below, are effectivemodulators of chemokine activity.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[1] Thus, in a first embodiment, the present invention provides novelcompounds of formula (I):

or stereoisomers or pharmaceutically acceptable salts thereof, wherein:

-   Ring D is a 6-membered ring heterocycle wherein B is O, S, or NR¹⁷    with the heterocycle further containing at least one carbonyl or    sulfonyl therein;-   R⁴ is selected from H, R⁵ and R¹³;-   R¹⁷ is selected from H, R⁵ and R¹⁸;-   with the proviso that Ring D contains at least one R⁵;-   Z is selected from O, S, NR^(1a), C(CN)₂, CH(NO₂), and CHCN;-   R^(1a) is selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,    CONR^(1b)R^(1b), OR^(1b), CN, NO₂, and (CH₂)_(w)phenyl;-   R^(1b) is independently selected from H, C₁₋₃ alkyl, C₃₋₆    cycloalkyl, and phenyl;-   E is —(CR⁷CR⁸)—(CR⁹R¹⁰)_(v)—(CR¹¹R¹²),    —(C═O)—(CR⁹R¹⁰)_(v)—(CR¹¹R¹²)—, —(SO₂)—(CR⁹R¹⁰)_(v)—(CR¹¹R¹²)—,-   Ring A is a C₃₋₈ carbocyclic residue;-   R¹ and R² are independently selected from H, C₁₋₈ alkyl, C₃₋₈    alkenyl, C₃₋₈ alkynyl, and a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue    substituted with 0-5 R^(a);-   R^(a), at each occurrence, is independently selected from C₁₋₄    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br,    I, F, (CF₂)_(r)CF3, NO₂, CN, (CH₂)_(r)NR^(b)R^(b), (CH₂)_(r)OH,    (CH₂)_(r)OR^(c), (CH₂)_(r)SH, (CH₂)_(r)SR^(c), (CH₂)_(r)C(O)R^(b),    (CH₂)_(r)C(O)NR^(b)R^(b), (CH₂)_(r)NR^(b)C(O)R^(b),    (CH₂)_(r)C(O)OR^(b), (CH₂)_(r)OC(O)R^(c),    (CH₂)_(r)CH(═NR^(b))NR^(b)R^(b), (CH₂)_(r)NHC(═NR^(b))NR^(b)R^(b),    (CH₂)_(r)S(O)_(p)R^(c), (CH₂)_(r)S(O)₂NR^(b)R^(b),    (CH₂)_(r)NR^(b)S(O)₂R^(c), and (CH₂)_(r)phenyl;-   R^(b), at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₃₋₆ cycloalkyl, and phenyl;-   R^(c), at each occurrence, is independently selected from C₁₋₆    alkyl, C₃₋₆ cycloalkyl, and phenyl;-   R³ is selected from a (CR^(3a)R^(3b))_(r)—C₃₋₈ carbocyclic residue    substituted with 0-5 R¹⁵; and a (CR^(3a)R^(3a))_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R¹⁵;-   R^(3a) and R^(3b), at each occurrence, are independently selected    from H, C₁₋₆alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and phenyl;-   R⁵ is selected from a (CR^(5a)R^(5b))_(t)—C₃₋₁₀ carbocyclic residue    substituted with 0-5 R¹⁶ and a (CR^(5a)R^(5b))_(t-5-10) membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R¹⁶;-   R^(5a) and R^(5b), at each occurrence, are selected from H, C₁₋₆    alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and phenyl;-   R⁷, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,    (CH₂)_(q)OH, (CH₂)_(q)SH, (CH₂)_(q)OR^(7d), (CH₂)_(q)SR^(7d),    (CH₂)_(q)NR^(7a)R^(7a), (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(7b),    (CH₂)_(r)C(O)NR^(7a)R^(7a), (CH₂)_(q)NR^(7a)C(O)R^(7a),    (CH₂)_(q)NR^(7a)C(O)H, (CH₂)_(r)C(O)OR^(7b), (CH₂)_(q)OC(O)R^(7b),    (CH₂)_(q)S(O)_(p)R^(7b), (CH₂)_(q)S(O)₂NR^(7a)R^(7a),    (CH₂)_(q)NR^(7a)S(O)₂R^(7b), C₁₋₆ haloalkyl, a (CH₂)_(r)—C₃₋₁₀    carbocyclic residue substituted with 0-3 R^(7c), and a    (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-2 R^(7c);-   R^(7a), at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, a    (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(7e), and    a (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(7e);-   R^(7b), at each occurrence, is independently selected from C₁₋₆    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic    residue substituted with 0-2 R^(7e), and a (CH₂)_(r)-5-6 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(7e);-   R^(7c), at each occurrence, is independently selected from C₁₋₆    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br,    I, F, (CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(7f)R^(7f), (CH₂)_(r)OH,    (CH₂)_(r)OC₁₋₄ alkyl, (CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH,    (CH₂)_(r)C(O)R^(7b), (CH₂)_(r)C(O)NR^(7f)R^(7f),    (CH₂)_(r)NR^(7f)C(O)R^(7a), (CH₂)_(r)C(O)OC₁₋₄ alkyl,    (CH₂)_(r)OC(O)R^(7b), (CH₂)_(r)C(═NR^(7f))NR^(7f)R^(7f),    (CH₂)_(r)S(O)_(p)R^(7b), (CH₂)_(r)NHC(═NR^(7f))NR^(7f)R^(7f),    (CH₂)_(r)S(O)₂NR^(7f)R^(7f), (CH₂)_(r)NR^(7f)S (O)₂R^(7b), and    (CH₂)_(r)phenyl substituted with 0-3 R^(7e);-   R^(7d), at each occurrence, is independently selected from methyl,    CF₃ C₂₋₆ alkyl substituted with 0-3 R^(7e), alkenyl, alkynyl, and a    C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(7c);-   R^(7e), at each occurrence, is independently selected from C₁₋₆    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I,    CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅    alkyl, (CH₂)_(r)NR^(7f)R^(7f), and (CH₂)_(r)phenyl;-   R^(7f), at each occurrence, is independently selected from H, C₁₋₆    alkyl, and C₃₋₆ cycloalkyl;-   R⁸ is selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and    (CH₂)_(r)phenyl substituted with 0-3 R^(8a);-   R^(8a), at each occurrence, is independently selected from C₁₋₆    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I,    CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅    alkyl, (CH₂)_(r)NR^(8f)R^(8f), and (CH₂)_(r)phenyl;-   alternatively, R⁷ and R⁸ join to form C₃₋₇ cycloalkyl, or ═NR^(8b);-   R^(8b) is selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, OH, CN, and    (CH₂)_(r)-phenyl;-   R^(8f), at each occurrence, is independently selected from H, C₁₋₆    alkyl, and C₃₋₆ cycloalkyl;-   R⁹, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, F,    Cl, Br, I, NO₂, CN, (CHR′)_(r)OH, (CHR′)_(r)OR^(9d),    (CHR′)_(r)SR^(9d), (CHR′)_(r)NR^(9a)R^(9a), (CHR′)_(r)C(O)OH,    (CHR′)_(r)C(O)R^(9b), (CHR′)_(r)C(O)NR^(9a)R^(9a),    (CHR′)_(r)NR^(9a)C(O)R^(9b), (CHR′)_(r)NR^(9a)C(O)H,    (CHR′)_(r)C(O)OR^(9b), (CHR′)_(r)OC(O)R^(9b),    (CHR′)_(r)OC(O)NR^(9a)R^(9a), (CHR′)_(r)NR^(9a)C(O)OR^(9b),    (CHR′)_(r)S(O)_(p)R^(9b), (CHR′)_(r)S(O)₂NR^(9a)R^(9a),    (CHR′)_(r)NR^(9a)S(O)₂R^(9b), C₁₋₆ haloalkyl, a (CHR′)_(r)—C₃₋₁₀    carbocyclic residue substituted with 0-5 R^(9c), and a    (CHR′)_(r)-5-10 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(9c);-   R^(9a) at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic    residue substituted with 0-5 R^(9e), and a (CH₂)_(r)-4-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(9e);-   alternatively, two R^(9a)s, along with the N to which they are    attached, join to form a 5-6 membered heterocyclic system containing    1-2 heteroatoms selected from NR^(9g), O, and S and optionally fused    with a benzene ring or a 6-membered aromatic heterocycle;-   R^(9b), at each occurrence, is independently selected from C₁₋₆    alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic    residue substituted with 0-2 R^(9e), and a (CH₂)_(r)-4-6 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(9e);-   R^(9c), at each occurrence, is independently selected from C₁₋₆    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br,    I, F, (CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(9f)R^(9f), (CH₂)_(r)OH,    (CH₂)_(r)OR^(9b), (CH₂)_(r)SR^(9b), (CH₂)_(r)C(O)OH,    (CH₂)_(r)C(O)R^(9b), (CH₂)_(r)C(O)NR^(9f)R^(9f),    (CH₂)_(r)NR^(9f)C(O)R^(9b), (CH₂)_(r)C(O)OR^(9b),    (CH₂)_(r)OC(O)R^(9b), (CH₂)_(r)C(═NR^(9f))NR^(9f)R^(9f),    (CH₂)_(r)S(O)_(p)R^(9b), (CH₂)_(r)NHC(═NR^(9f))NR^(9f)R^(9f),    (CH₂)_(r)S(O)₂NR^(9f)R^(9f), (CH₂)_(r)NR^(9f)S(O)₂R^(9b), and    (CH₂)_(r)phenyl substituted with 0-3 R^(9e);-   R^(9d), at each occurrence, is independently selected from methyl,    CF₃, C₂₋₆ alkyl residue substituted with 0-3 R^(9e), C₃₋₆ alkenyl,    C₃₋₆ alkynyl, a C₃₋₁₀ carbocyclic residue substituted with 0-3    R^(9c), and a 5-6 membered heterocyclic system containing 1-4    heteroatoms selected from the group consisting of N, O, and S    substituted with 0-3 R^(9c);-   R^(9e), at each occurrence, is independently selected from C₁₋₆    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F,    Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH,    (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(9f)R^(9f), and (CH₂)_(r)phenyl,    wherein the phenyl on the (CH₂)_(r)phenyl is substituted with 0-5    substituents selected from F, Cl, Br, I, NO₂, C₁₋₆alkyl, OH, and    NR^(9f)R^(9f);-   R^(9f), at each occurrence, is independently selected from H, C₁₋₆    alkyl, and C₃₋₆ cycloalkyl;-   R^(9g) is selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,    (CH₂)_(r)phenyl, C(O)R^(9f), C(O)OR^(9h), and SO₂R⁹ h;-   R^(9h), at each occurrence, is independently selected from C₁₋₆    alkyl, and C₃₋₆ cycloalkyl;-   R¹⁰, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, F,    Cl, Br, I, NO₂, CN, (CHR′)_(r)OH, (CH₂)_(r)OR^(10d),    (CH₂)_(r)SR^(10d), (CH₂)_(r)NR^(10a)R^(10a), (CH₂)_(r)C(O)OH,    (CH₂)_(r)C(O)R^(10b), (CH₂)_(r)C(O)NR^(10a)R^(10a),    (CH₂)_(r)NR^(10a)C(O)R^(10a), (CH₂)_(r)NR^(10a)C(O)H,    (CH₂)_(r)C(O)OR^(10b), (CH₂)_(r)OC(O)R^(10b),    (CH₂)_(r)OC(O)NR^(10a)R^(10a), (CH₂)_(r)NR^(10a)C(O)OR^(10b),    (CH₂)_(r)S(O)_(p)R^(10b), (CH₂)_(r)S(O)₂NR^(10a)R^(10a),    (CH₂)_(r)NR^(10a)S(O)₂R^(10b), C₁₋₆ haloalkyl, a (CH₂)_(r)—C₃₋₁₀    carbocyclic residue substituted with 0-5 R^(10c), and a    (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(10c);-   R^(10a), at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic    residue substituted with 0-5 R^(10e), and a (CH₂)_(r)-4-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(10e);-   alternatively, two R¹⁰ as, along with the N to which they are    attached, join to form a 5-6 membered heterocyclic system containing    1-2 heteroatoms selected from NR_(10g), O, and S and optionally    fused with a benzene ring or a 6-membered aromatic heterocycle;-   R^(10b), at each occurrence, is independently selected from C₁₋₆    alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic    residue substituted with 0-2 R^(10e), and a (CH₂)_(r)-4-6 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(10e);-   R^(10c), at each occurrence, is independently selected from C₁₋₆    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br,    I, F, (CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(10f)R^(10f), (CH₂)_(r)OH,    (CH₂)_(r)OR^(10b), (CH₂)_(r)SR^(10b), (CH₂)_(r)C(O)OH,    (CH₂)_(r)C(O)R^(10b), (CH₂)_(r)C(O)NR^(10f)R^(10f),    (CH₂)_(r)NR^(10f)C(O)R^(10a), (CH₂)_(r)C(O)OR^(10b),    (CH₂)_(r)OC(O)R^(10b), (CH₂)_(r)C(═NR^(10f))NR^(10f)R^(10f),    (CH₂)_(r)S(O)_(p)R^(10b), (CH₂)_(r)NHC(═NR^(10f))NR^(10f)R^(10f),    (CH₂)_(r)S(O)₂NR^(10f)R^(10f), (CH₂)_(r)NR^(10f)S(O)₂R^(10b), and    (CH₂)_(r)phenyl substituted with 0-3 R^(10e);-   R^(10d), at each occurrence, is independently selected from methyl,    CF₃, C₂₋₆ alkyl substituted with 0-3 R^(10e), C₃₋₆ alkenyl, C₃₋₆    alkynyl, and a C₃₋₁₀ carbocyclic residue substituted with 0-3    R^(10c);-   R^(10e), at each occurrence, is independently selected from C₁₋₆    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F,    Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH,    (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(10f)R^(10f), and (CH₂)_(r)phenyl;-   R^(10f), at each occurrence, is independently selected from H, C₁₋₆    alkyl, and C₃₋₆ cycloalkyl;-   R^(10g) is selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,    (CH₂)_(r)phenyl, C(O)R^(10f), SO₂R^(10h), and C(O)O R^(10h);-   R^(10h), at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₃₋₆ cycloalkyl;-   alternatively, R⁹ and R¹⁰ join to form ═O, a C₃₋₁₀ cycloalkyl, a    5-6-membered lactone or lactam, or a 4-6-membered saturated    heterocycle containing 1-2 heteroatoms selected from O, S, and    NR^(10g) and optionally fused with a benzene ring or a 6-membered    aromatic heterocycle;-   R¹¹, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,    (CR′R′)_(q)OH, (CH₂)_(q)SH, (CR′R′)_(q)OR^(11d), (CHR′)_(q)SR^(11d),    (CR′R′)_(q)NR^(11a)R^(11a), (CHR′)_(r)C(O)OH, (CHR′)_(r)C(O)R^(11b),    (CHR′)_(r)C(O)NR^(11a)R^(11a), (CHR′)_(q)NR^(11a)C(O)R^(11a),    (CHR′)_(q)OC(O)NR^(11a)R^(11a), (CHR′)_(q)NR^(11a)C(O)OR^(11b),    (CHR′)_(q)NR^(11a)C(O)NHR^(11a), (CHR′)_(r)C(O)OR^(11b),    (CHR′)_(q)OC(O)R^(11b), (CHR′)_(q)S(O)_(p)R^(11b),    (CHR′)_(q)S(O)₂NR^(11a)R^(11a), (CHR′)_(q)NR^(11a)S(O)₂R^(11b), C₁₋₆    haloalkyl, a (CHR′)_(r)—C₃₋₁₀ carbocyclic residue substituted with    0-5 R^(11c), and a (R′R¹⁷)_(r)-5-10 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-3 R^(11c);-   R^(11a), at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic    residue substituted with 0-5 R^(11e), and a (CH₂)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(11e);-   alternatively, two R^(11a)s, along with the N to which they are    attached, join to form a 5-6 membered heterocyclic system containing    1-2 heteroatoms selected from NR^(11g), O, and S and optionally    fused with a benzene ring or a 6-membered aromatic heterocycle;-   R^(11b), at each occurrence, is independently selected from C₁₋₆    alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic    residue substituted with 0-2 R^(11e), and a (CH₂)_(r)-4-6 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(11e);-   R^(11c), at each occurrence, is independently selected from C₁₋₆    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br,    I, F, (CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(11f)R^(11f), (CH₂)_(r)OH,    (CH₂)_(r)OC₁₋₄ alkyl, (CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH,    (CH₂)_(r)C(O)R^(11b), (CH₂)_(r)C(O)NR^(11f)R^(11f),    (CH₂)_(r)NR^(11f)C(O)R^(11a), (CH₂)_(r)C(O)OC₁₋₄ alkyl,    (CH₂)_(r)OC(O)R^(11b), (CH₂)_(r)C(═NR^(11f))NR^(11f)R^(11f),    (CH₂)_(r)NHC(═NR^(11f))NR^(11f)R^(11f), (CH₂)_(r)S(O)_(p)R^(11b),    (CH₂)_(r)S(O)₂NR^(11f)R^(11f), (CH₂)_(r)NR^(11f)S(O)₂R^(11b), and    (CH₂)_(r)phenyl substituted with 0-3 R^(11e);-   R^(11d), at each occurrence, is independently selected from methyl,    CF₃, C₂₋₆ alkyl substituted with 0-3 R^(11e), C₃₋₆ alkenyl, C₃₋₆    alkynyl, and a C₃₋₁₀ carbocyclic residue substituted with 0-3    R^(11c);-   R^(11e), at each occurrence, is independently selected from C₁₋₆    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I,    CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅    alkyl, (CH₂)_(r)NR^(11f)R^(11f), and (CH₂)_(r)phenyl, wherein the    phenyl on the (CH₂)_(r)phenyl is substituted with 0-5 substituents    selected from F, Cl, Br, I, NO₂, C₁₋₆alkyl, OH, and NR^(11f)R^(11f);-   R^(11f), at each occurrence, is independently selected from H, C₁₋₆    alkyl, and C₃₋₆ cycloalkyl;-   R¹¹ g is selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,    (CH₂)_(r)phenyl, C(O)R^(11f), C(O)OR^(11h), and SO₂R^(11h);-   R^(11h), at each occurrence, is independently selected from C₁₋₆    alkyl, and C₃₋₆ cycloalkyl;-   R¹², is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,    (CHR′)_(q)OH, (CH₂)_(q)SH, (CHR′)_(q)OR^(12d), (CH₂)_(q)SR^(12d),    (CHR′)_(q)NR^(12a)R^(12a), (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(12b),    (CH₂)_(r)C(O)NR^(12a)R^(12a), (CH₂)_(q)NR^(12a)C(O)R^(12a),    (CH₂)_(r)OC(O)NR^(12a)R^(12a), (CH₂)_(r)NR^(12a)C(O)OR^(12b),    (CH₂)_(q)NR^(12a)C(O)NHR^(12a), (CH₂)_(r)C(O)OR^(12b),    (CH₂)_(q)OC(O)R^(12b), (CH₂)_(q)S(O)_(p)R^(12b),    (CH₂)_(q)S(O)₂NR^(12a)R^(12a), (CH₂)_(q)NR^(12a)S(O)₂R^(12b), C₁₋₆    haloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with    0-5 R^(12c), and a (CR′R¹⁷)_(r)-5-10 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-3 R^(12c);-   R^(12a), at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic    residue substituted with 0-5 R^(12e), and a (CH₂)_(r)-4-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(12e);-   alternatively, two R^(12a)s, along with the N to which they are    attached, join to form a 5-6 membered heterocyclic system containing    1-2 heteroatoms selected from NR^(12g), O, and S and optionally    fused with a benzene ring or a 6-membered aromatic heterocycle;-   R^(12b), at each occurrence, is independently selected from C₁₋₆    alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic    residue substituted with 0-2 R^(12e), and a (CH₂)_(r)-4-6 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(12e);-   R^(12c), at each occurrence, is independently selected from C₁₋₆    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br,    I, F, (CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(12f)R^(12f), (CH₂)_(r)OH,    (CH₂)_(r)OC₁₋₄ alkyl, (CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH,    (CH₂)_(r)C(O)R^(12b), (CH₂)_(r)C(O)NR^(12f)R^(12f),    (CH₂)_(r)NR^(12f)C(O)R^(12a), (CH₂)_(r)C(O)OC₁₋₄ alkyl,    (CH₂)_(r)OC(O)R^(12b), (CH₂)_(r)C(═NR^(12f))NR^(12f)R^(12f),    (CH₂)_(r)NHC(═NR^(12f))NR^(12f)R^(12f), (CH₂)_(r)S(O)_(p)R^(12b),    (CH₂)_(r)S(O)₂NR^(12f)R^(12f), (CH₂)_(r)NR^(12f)S(O)₂R^(12b), and    (CH₂)_(r)phenyl substituted with 0-3 R^(12e);-   R^(12d), at each occurrence, is independently selected from methyl,    CF₃, C₂₋₆ alkyl substituted with 0-3 R^(12e), C₃₋₆ alkenyl, C₃₋₆    alkynyl, and a C₃₋₁₀ carbocyclic residue substituted with 0-3    R^(12c);-   R^(12e), at each occurrence, is independently selected from C₁₋₆    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I,    CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅    alkyl, (CH₂)_(r)NR^(12f)R^(12f), and (CH₂)_(r)phenyl;-   R^(12f), at each occurrence, is independently selected from H, C₁₋₆    alkyl, and C₃₋₆ cycloalkyl;-   R^(12g) is selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,    (CH₂)_(r)phenyl, C(O)R^(12f), C(O)OR^(12h), and SO₂R^(12h);-   R^(12h), at each occurrence, is independently selected from C₁₋₆    alkyl, and C₃₋₆ cycloalkyl;-   alternatively, R¹¹ and R¹² join to form a C₃₋₁₀ cycloalkyl, a    5-6-membered lactone or lactam, or a 4-6-membered saturated    heterocycle containing 1-2 heteroatoms selected from O, S, and NR¹¹    g and optionally fused with a benzene ring or a 6-membered aromatic    heterocycle;-   R¹³, at each occurrence, is independently selected from C₁₋₆ alkyl,    C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, (CF₂)_(w)CF₃,    (CH₂)_(q)NR^(13a)R^(13a), (CHR′)_(q)OH, (CH₂)_(q)OR^(13b),    (CH₂)_(q)SH, (CH₂)_(q)SR^(13b), (CH₂)_(w)C(O)OH,    (CH₂)_(w)C(O)R^(13b), (CH₂)_(w)C(O)NR^(13a)R^(13a),    (CH₂)_(q)NR^(13d)C(O)R^(13a), (CH₂)_(w)C(O)OR^(13b),    (CH₂)_(q)OC(O)R^(13b), (CH₂)_(w)S(O)_(p)R^(13b),    (CH₂)_(w)S(O)₂NR^(13a)R^(13a), (CH₂)_(q)NR^(13d)S(O)₂R^(13b), and    (CH₂)_(w)-phenyl substituted with 0-3 R^(13c);-   R^(13a), at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₃₋₆ cycloalkyl, and phenyl substituted with 0-3 R^(13c);-   R^(13b), at each occurrence, is independently selected from C₁₋₆    alkyl, C₃₋₆ cycloalkyl, and phenyl substituted with 0-3 R^(13c);-   R^(13c), at each occurrence, is independently selected from C₁₋₆    alkyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,    (CH₂)_(r)OC₁₋₅ alkyl, (CH₂)_(r)OH, (CH₂)_(r)SC₁₋₅ alkyl, and    (CH₂)_(r)NR^(13d)R^(13d);-   R^(13d), at each occurrence, is independently selected from H, C₁₋₆    alkyl, and C₃₋₆ cycloalkyl;-   R¹⁴, at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br,    I, F, NO₂, CN, (CHR′)_(r)NR^(14a)R^(14a), (CHR′)_(r)OH,    (CHR′)_(r)O(CHR′)_(r)R^(14d), (CHR′)_(r)SH, (CHR′)_(r)C(O)H,    (CHR′)_(r)S(CHR′)_(r)R^(14d), (CHR′)_(r)C(O)OH,    (CHR′)_(r)C(O)(CHR′)_(r)R^(14b), (CHR′)_(r)C(O)NR^(14a)R^(14a),    (CHR′)_(r)NR^(14f)C(O) (CHR′)_(r)R^(14b),    (CHR′)_(r)OC(O)NR^(14a)R^(14a),    (CHR′)_(r)NR^(14f)C(O)O(CHR′)_(r)R^(14b),    (CHR′)_(r)C(O)O(CHR′)_(r)R^(14d), (CHR′)_(r)OC(O) (CHR′)_(r)R^(14b),    (CHR′)_(r)C(═NR^(14f))NR^(14a)R^(14a),    (CHR′)_(r)NHC(═NR^(14f))NR^(14f)R^(14f),    (CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(14b), (CHR′)_(r)S(O)₂NR^(14a)R^(14a),    (CHR′)_(r)NR^(14f)S(O)₂(CHR′)_(r)R^(14b), C₁₋₆ haloalkyl, C₂₋₈    alkenyl substituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3    R′, (CHR′)_(r)phenyl substituted with 0-3 R^(14e), and a    (CH₂)_(r)-4-10 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-2 R^(15e),    or two R¹⁴ substituents on adjacent atoms on ring A form to join a    5-6 membered heterocyclic system containing 1-3 heteroatoms selected    from N, O, and S substituted with 0-2 R^(15e);-   R^(14a), at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic    residue substituted with 0-5 R^(14e), and a (CH₂)_(r)-4-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-2 R^(14e);-   R^(14b), at each occurrence, is independently selected from C₁₋₆    alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic    residue substituted with 0-3 R^(14e), and (CH₂)_(r)-4-6 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-2 R^(14e);-   R^(14d), at each occurrence, is independently selected from C₃₋₈    alkenyl, C₃₋₈ alkynyl, methyl, CF₃, C₂₋₆ alkyl substituted with 0-3    R^(14e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3    R^(14e), and a (CH₂)_(r)4-6 membered heterocyclic system containing    1-4 heteroatoms selected from N, O, and S, substituted with 0-3    R^(14e);-   R^(14e), at each occurrence, is independently selected from C₁₋₆    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F,    Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH,    (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(14f)R^(14f), and (CH₂)_(r)phenyl;-   R^(14f), at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₃₋₆ cycloalkyl, and phenyl;-   R¹⁵, at each occurrence, is independently selected from C₁₋₈ alkyl,    (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,    (CR′R′)_(r)NR^(15a)R^(15a), (CR′R′)_(r)OH,    (CR′R′)_(r)O(CHR′)_(r)R^(15d), (CR′R′)_(r)SH, (CR′R′)_(r)C(O)H,    (CR′R′)_(r)S(CHR′)_(r)R^(15d), (CR′R′)_(r)C(O)OH, (CR′R′)_(r)C(O)    (CHR′)_(r)R^(15b), (CR′R′)_(r)C(O)NR^(15a)R^(15a),    (CR′R′)_(r)NR^(15f)C(O) (CHR′)_(r)R^(15b),    (CR′R′)_(r)OC(O)NR^(15a)R^(15a),    (CR′R′)_(r)NR^(15f)C(O)O(CHR′)_(r)R^(15b),    (CR′R′)_(r)NR^(15f)C(O)NR^(15f)R^(15f),    (CR′R′)_(r)C(O)O(CHR′)_(r)R^(15d), (CR′R′)_(r)OC(O)    (CHR′)_(r)R^(15b), (CR′R′)_(r)C(═NR^(15f))NR^(15a)R^(15a),    (CR′R′)_(r)NHC(═NR^(15f))NR^(15f)R^(15f),    (CR′R′)_(r)S(O)_(p)(CHR′)_(r)R^(15b),    (CR′R′)_(r)S(O)₂NR^(15a)R^(15a),    (CR′R′)_(r)NR^(15f)S(O)₂(CHR′)_(r)R^(15b), C₁₋₆ haloalkyl, C₂₋₈    alkenyl substituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3    R′, (CR′R′)_(r)phenyl substituted with 0-3 R^(15e), and a    (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-2 R^(15e);-   R^(15a), at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic    residue substituted with 0-5 R^(15e), and a (CH₂)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-2 R^(15e);-   alternatively, two R^(15a)s, along with the N to which they are    attached, join to form a 5-6 membered heterocyclic system containing    1-2 heteroatoms selected from NR^(15h), O, and S and optionally    fused with a benzene ring or a 6-membered aromatic heterocycle;-   R^(15b), at each occurrence, is independently selected from C₁₋₆    alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic    residue substituted with 0-3 R^(15e), and (CH₂)_(r)-5-6 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-2 R^(15e);-   R^(15d), at each occurrence, is independently selected from C₃₋₈    alkenyl, C₃₋₈ alkynyl, methyl, CF₃, C₂₋₆ alkyl substituted with 0-3    R^(15e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3    R^(15e), and a (CH₂)_(r5-6) membered heterocyclic system containing    1-4 heteroatoms selected from N, O, and S, substituted with 0-3    R^(15e);-   R^(15e), at each occurrence, is independently selected from C₁₋₆    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F,    Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH,    (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(15f)R^(15f), (CH₂)_(r)phenyl, and    a heterocycle substituted with 0-1 R^(15g), wherein the heterocycle    is selected from imidazole, thiazole, oxazole, pyrazole,    1,2,4-triazole, 1,2,3-triazole, isoxazole, and tetrazole;-   R^(15f), at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₃₋₆ cycloalkyl, and phenyl;-   R^(15g) is selected from methyl, ethyl, acetyl, and CF₃;-   R^(15h) is selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,    (CH₂)_(r)phenyl, C(O)R^(15f), C(O)OR^(15i), and SO₂R^(15i);-   R^(15i), at each occurrence, is independently selected from C₁₋₆    alkyl, C₃₋₆ cycloalkyl;-   R¹⁶, at each occurrence, is independently selected from C₁₋₈ alkyl,    C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F,    NO₂, CN, (CHR′)_(r)NR^(16a)R^(16a), (CHR′)_(r)OH,    (CHR′)_(r)O(CHR′)_(r)R^(16d), (CHR′)_(r)SH, (CHR′)_(r)C(O)H,    (CHR′)_(r)S(CHR′)_(r)R^(16d), (CHR′)_(r)C(O)OH, (CHR′)_(r)C(O)    (CHR′)_(r)R^(16b), (CHR′)_(r)C(O)NR^(16a)R^(16a),    (CHR′)_(r)NR^(16f)C(O) (CHR′)_(r)R^(16b),    (CHR′)_(r)C(O)O(CHR′)_(r)R^(16d), (CHR′)_(r)OC(O) (CHR′)_(r)R^(16b),    (CHR′)_(r)C(═NR^(16f))NR^(16a)R^(16a),    (CHR′)_(r)NHC(═NR^(16f))NR^(16f)R^(16f),    (CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(16b), (CHR′)_(r)S(O)₂NR^(16a)R^(16a),    (CHR′)_(r)NR^(16f)S(O)₂(CHR′)_(r)R^(16b), C₁₋₆ haloalkyl, C₂₋₈    alkenyl substituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3    R′, and (CHR′)_(r)phenyl substituted with 0-3 R^(16e);-   R^(16a), at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic    residue substituted with 0-5 R^(16e), and a (CH₂)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-2 R^(16e);-   R^(16b), at each occurrence, is independently selected from C₁₋₆    alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a (CH₂)_(r)C₃₋₆ carbocyclic    residue substituted with 0-3 R^(16e), and a (CH₂)_(r)-5-6 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-2 R^(16e);-   R^(16d), at each occurrence, is independently selected from C₃₋₈    alkenyl, C₃₋₈ alkynyl, methyl, CF₃, C₂₋₆ alkyl substituted with 0-3    R^(16e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3    R^(16e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing    1-4 heteroatoms selected from N, O, and S, substituted with 0-3    R^(16e);-   R^(16e), at each occurrence, is independently selected from C₁₋₆    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F,    Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH,    (CH₂)_(r)SC₁₋₁₅ alkyl, (CH₂)_(r)NR^(16f)R_(16f), and    (CH₂)_(r)phenyl;-   R^(16f), at each occurrence, is independently selected from H, C₁₋₅    alkyl, and C₃₋₆ cycloalkyl, and phenyl;-   R′, at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and    (CH₂)_(r)phenyl substituted with R^(e);-   R^(e) is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,    (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,    (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,    (CH₂)_(r)NR^(f)R^(f), and (CH₂)_(r)phenyl;-   R^(f) is selected from H, C₁₋₅ alkyl, and C₃₋₆ cycloalkyl, and    phenyl;-   R¹⁸, at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₃₋₆ alkenyl, C₃₋₆ alkynyl, C(O)—C₃₋₆ alkyl, C(O)—C₃₋₆    alkenyl, C(O)—C₃₋₆ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and    (CH₂)_(r)phenyl substituted with R^(e);-   R¹⁹ is absent, taken with the nitrogen to which it is attached to    form an N-oxide, or selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈    alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, (CH₂)_(q)C(O)R^(19b),    (CH₂)_(q)C(O)NR^(19a)R^(19a), (CH₂)_(q)C(O)OR^(19b), and a    (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(19c);-   R^(19a), at each occurrence, is selected from H, C₁₋₆ alkyl,    (CH₂)_(r)C₃₋₆ cycloalkyl, and phenyl;-   R^(19b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, (CH₂)_(r)C₃₋₆ cycloalkyl, C₂₋₈ alkynyl, and phenyl;-   R^(19c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,    (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, (CH₂)_(r)OH, (CH₂)_(r)SC₁₋₅    alkyl, (CH₂)_(r)NR^(19a)R^(19a), and (CH₂)_(r)phenyl;-   alternatively, R¹⁹ joins with R⁷, R⁹, or R¹¹ to form a 5, 6 or 7    membered piperidinium spirocycle or pyrrolidinium spirocycle    substituted with 0-3 R^(a);-   g is selected from 0, 1, 2, and 3;-   v is selected from 0, 1, and 2;-   t is selected from 1 and 2;-   w is selected from 0 and 1;-   r is selected from 0, 1, 2, 3, 4, and 5;-   q is selected from 1, 2, 3, 4, and 5; and-   p is selected from 0, 1, and 2.-   In another embodiment, the present invention provides compounds of    formula (I), wherein-   ring D is selected from-   Z is selected from O, S, N(CN), and N(CONH₂);-   R¹ and R² are independently selected from H and C₁₋₄ alkyl;-   R¹⁹ is absent, taken with the nitrogen to which it is attached to    form an N-oxide, or selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆    cycloalkyl, and (CH₂)_(r)-phenyl substituted with 0-3 R^(19c);-   R^(19c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,    (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, (CH₂)_(r)OH, (CH₂)_(r)SC₁₋₅    alkyl, (CH₂)_(r)NR^(19a)R⁹, and (CH₂)_(r)phenyl;-   alternatively, R¹⁹ joins with R⁷, R⁹, or R¹¹ to form a 5, 6 or 7    membered piperidinium spirocycle or pyrrolidinium spirocycle    substituted with 0-3 R^(a);-   R¹³, at each occurrence, is independently selected from C₁₋₄ alkyl,    C₃₋₆ cycloalkyl, (CH₂)NR^(13a)R^(13a), (CHR′)OH, (CH₂)OR^(13b),    (CH₂)_(w)C(O)R^(13b), (CH₂)_(w)C(O)NR^(13a)R^(13a),    (CH₂)NR^(13d)C(O)R^(13a), (CH₂)_(w)S(O)₂NR^(13a)R^(13a),    (CH₂)NR^(13d)S(O)₂R^(13b), and (CH₂)_(w)-phenyl substituted with 0-3    R^(13c);-   R^(13a), at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₃₋₆ cycloalkyl, and phenyl substituted with 0-3 R^(13c);-   R^(13b), at each occurrence, is independently selected from C₁₋₆    alkyl, C₃₋₆ cycloalkyl, and phenyl substituted with 0-3 R^(13c);-   R^(13c), at each occurrence, is independently selected from C₁₋₆    alkyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,    (CH₂)_(r)OC₁₋₅ alkyl, (CH₂)_(r)OH, and (CH₂)_(r)NR^(13d)R^(13d);-   R^(13d), at each occurrence, is independently selected from H, C₁₋₆    alkyl, and C₃₋₆ cycloalkyl;-   q is selected from 1, 2, and 3; and-   r is selected from 0, 1, 2, and 3.-   In another embodiment, the present invention provides compounds of    formula (I), wherein-   E is —(C═O)—(CR⁹R¹⁰)_(v)—(CR¹¹R¹²)—,    —(CR⁷R⁸)—(CR⁹R¹⁰)_(v)—(CR¹¹R¹²),-   R³ is selected from a (CR^(3a)H)_(r)—C₃₋₈ carbocyclic residue    substituted with 0-5 R¹⁵, wherein the carbocyclic residue is    selected from phenyl, C₃₋₆ cycloalkyl, naphthyl, and adamantyl; and    a (CR^(3a)H)_(r)-heterocyclic system substituted with 0-3 R¹⁵,    wherein the heterocyclic system is selected from pyridinyl,    thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl,    benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl,    quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl,    indazolyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl,    pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl,    thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; and-   R⁵ is selected from (CR^(5a)H)_(t)-phenyl substituted with 0-5 R¹⁶;    and a (CR^(5a)H)_(t)-heterocyclic system substituted with 0-3 R¹⁶,    wherein the heterocyclic system is selected from pyridinyl,    thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl,    benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl,    quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl,    isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl,    1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl,    thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl.-   In another embodiment, the present invention provides compounds of    formula (I), wherein-   B is selected from O and NR¹⁷.-   E is —(CR⁷R⁸)—(CR⁹R¹⁰)_(v)—(CR¹¹R¹²),-   R¹ and R² are H;-   R¹⁶, at each occurrence, is independently selected from C₁₋₈ alkyl,    (CH₂)_(r)C₃₋₆ cycloalkyl, CF₃, Cl, Br, I, F,    (CH₂)_(r)NR^(16a)R^(16a), NO₂, CN, OH, (CH₂)_(r)OR^(16d),    (CH₂)_(r)C(O)R^(16b), (CH₂)_(r)C(O)NR^(16a)R^(16a),    (CH₂)_(r)NR^(16f)C(O)R^(16b), (CH₂)_(r)S(O)_(p)R^(16b),    (CH₂)_(r)S(O)₂NR^(16a)R^(16a), (CH₂)_(r)NR^(16f)S(O)₂R^(16b), and    (CH₂)_(r)phenyl substituted with 0-3 R^(16e);-   R^(16a), at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3    R^(16e);-   R^(16b), at each occurrence, is independently selected from C₁₋₆    alkyl, C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3    R^(16e);-   R^(16d), at each occurrence, is independently selected from C₁₋₆    alkyl and phenyl;-   R^(16e), at each occurrence, is independently selected from C₁₋₆    alkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₁₅    alkyl; and-   R^(16f), at each occurrence, is independently selected from H, and    C₁₋₅ alkyl.

In another embodiment, the present invention provides compounds offormula (I), wherein

-   E is —(CR⁷R⁸)—(CR⁹R¹⁰)_(n)—(CR¹¹R¹²)-   B is selected from NR¹⁷ or O;-   R⁵ is CH₂phenyl substituted with 0-3 R¹⁶; and-   r is selected from 0, 1, and 2.-   In another embodiment, the present invention provides compounds of    formula (I), wherein-   Z is selected from O, N(CN) and NC(O)NH₂; and-   R⁴ is selected from H and R⁵.-   In another embodiment, the present invention provides compounds of    formula (I), wherein-   R³ is a C₃₋₁₀ carbocyclic residue substituted with 0-3 R¹⁵, wherein    the carbocyclic residue is selected from cyclopropyl, cyclopentyl,    cyclohexyl, phenyl, naphthyl and adamantyl, and a    (CR^(3a)H)_(r)-heterocyclic system substituted with 0-3 R¹⁵, wherein    the heterocyclic system is selected from pyridinyl, thiophenyl,    furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl,    benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl,    isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl,    isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl,    1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl,    thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; and-   R¹⁵, at each occurrence, is independently selected from C₁₋₈ alkyl,    (CH₂)_(r)C₃₋₆ cycloalkyl, CF₃, Cl, Br, I, F,    (CH₂)_(r)NR^(15a)R^(15a), NO₂, CN, OH, (CH₂)_(r)OR^(15d),    (CH₂)_(r)C(O)R^(15b), (CH₂)_(r)C(O)NR^(15a)R^(15a),    (CH₂)_(r)NR^(15f)C(O)R^(15b), (CH₂)_(r)OC(O)NR^(15a)R^(15a),    (CH₂)_(r)NR^(15f)C(O)OR^(15b), (CH₂)_(r)S(O)_(p)R^(15b),    (CH₂)_(r)S(O)₂NR^(15a)R^(15a), (CH₂)_(r)NR^(15f)S(O)₂R^(15b),    (CH₂)_(r)phenyl substituted with 0-3 R^(15e), and a (CH₂)_(r)-5-6    membered heterocyclic system containing 1-4 heteroatoms selected    from N, O, and S, substituted with 0-2 R^(15e);-   R^(15a), at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3    R^(15e);-   alternatively, two R^(15a)s, along with the N to which they are    attached, join to form a 5-6 membered heterocyclic system containing    1-2 heteroatoms selected from NR^(15g), O, and S and optionally    fused with a benzene ring or a 6-membered aromatic heterocycle;-   R^(15b), at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3    R^(15e);-   R^(15d), at each occurrence, is independently selected from C₁₋₆    alkyl and phenyl;-   R^(15e), at each occurrence, is independently selected from C₁₋₆    alkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅    alkyl; and-   R^(15f), at each occurrence, is independently selected from H, and    C₁₋₅ alkyl.-   In another embodiment, the present invention provides compounds of    formula (I), wherein-   Z is O, N(CN), and NC(O)NH₂;-   B is NR¹⁷ or O;-   R⁵ is CH₂phenyl substituted with 0-3 R¹⁶; and-   r is selected from 0, 1, and 2.-   In another embodiment, the present invention provides compounds of    formula (I), wherein-   Z is selected from O, N(CN) and NC(O)NH₂;-   R³ is a C₃₋₁₀ carbocyclic residue substituted with 0-3 R¹⁵, wherein    the carbocyclic residue is selected from cyclopropyl, cyclobutyl,    cyclopentyl, cyclohexyl, phenyl, naphthyl and adamantyl, and a    (CR^(3a)H)_(r)-heterocyclic system substituted with 0-3 R¹⁵, wherein    the heterocyclic system is selected from pyridinyl, thiophenyl,    furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl,    benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl,    isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl,    isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl,    1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl,    thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl;-   R¹⁵, at each occurrence, is independently selected from C₁₋₈ alkyl,    (CH₂)_(r)C₃₋₆ cycloalkyl, CF₃, Cl, Br, I, F,    (CH₂)_(r)NR^(15a)R^(15a), NO₂, CN, OH, (CH₂)_(r)OR^(15d),    (CH₂)_(r)C(O)R^(15b), (CH₂)_(r)C(O)NR^(15a)R^(15a),    (CH₂)_(r)NR^(15f)C(O)R^(15b), (CH₂)_(r)OC(O)NR^(15a)R^(15a),    (CH₂)_(r)NR^(15f)C(O)OR^(15b), (CH₂)_(r)S(O)_(p)R^(15b),    (CH₂)_(r)S(O)₂NR^(15a)R^(15a), (CH₂)_(r)NR^(15f)S(O)₂R^(15b),    (CH₂)_(r)phenyl substituted with 0-3 R^(15e), and a (CH₂)_(r)-5-6    membered heterocyclic system containing 1-4 heteroatoms selected    from N, O, and S, substituted with 0-2 R^(15e);-   R^(15a), at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3    R^(15e);-   alternatively, two R^(15a)s, along with the N to which they are    attached, join to form a 5-6 membered heterocyclic system containing    1-2 heteroatoms selected from NR^(15g), O, and S and optionally    fused with a benzene ring or a 6-membered aromatic heterocycle;-   R^(15b), at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3    R^(15e);-   R^(15d), at each occurrence, is independently selected from C₁₋₆    alkyl and phenyl;-   R^(15e), at each occurrence, is independently selected from C₁₋₆    alkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅    alkyl; and-   R^(15f), at each occurrence, is independently selected from H, and    C₁₋₅ alkyl.-   In another embodiment, the present invention provides compounds of    formula (I), wherein-    and-   A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,    and phenyl.-   In another embodiment, the present invention provides compounds of    formula (I), wherein-   E is selected from (C═O)—(CR⁹R¹⁰)_(v)—(CR¹¹R¹²)—,-   R³ is a C₃₋₁₀ carbocyclic residue substituted with 0-3 R¹⁵, wherein    the carbocyclic residue is selected from cyclopropyl, cyclobutyl,    cyclopentyl, cyclohexyl, phenyl, naphthyl and adamantyl, and a    (CR^(3a)H)_(r)-heterocyclic system substituted with 0-3 R¹⁵, wherein    the heterocyclic system is selected from pyridinyl, thiophenyl,    furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl,    benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl,    isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl,    isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl,    1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl,    thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl.-   In another embodiment, the present invention provides compounds of    formula (I), wherein-   E is (C═O)—(CR⁹R¹⁰)_(v)—(CR¹¹R¹²)—.-   In another embodiment, the present invention provides compounds of    formula (I), wherein-   A is selected from cyclopropyl, cyclobutyl, cyclopentyl cyclohexyl,    and phenyl.-   In another embodiment, the present invention provides compounds of    formula (I), wherein-   R⁹, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, F,    Cl, Br, I, NO₂, CN, (CHR′)_(r)OH, (CH₂)_(r)OR^(9d),    (CH₂)_(r)SR^(9d), (CH₂)_(r)NR^(9a)R^(9a), (CH₂)_(r)C(O)OH,    (CH₂)_(r)C(O)R^(9b), (CH₂)_(r)C (O)NR^(9a)R^(9a),    (CH₂)_(r)NR^(9a)C(O)R^(9b), (CH₂)_(r)NR^(9a)C(O)H,C₁₋₆ haloalkyl, a    (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(9c), and    a (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(9c);-   R^(9a), at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic    residue substituted with 0-5 R^(9e), and a (CH₂)_(r)-4-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(9e);-   alternatively, two R⁹ as, along with the N to which they are    attached, join to form a 5-6 membered heterocyclic system containing    1-2 heteroatoms selected from NR^(9g), O, and S and optionally fused    with a benzene ring or a 6-membered aromatic heterocycle;-   R¹⁰, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, F,    Cl, Br, I, NO₂, CN, (CHR′)_(r)OH, (CH₂)_(r)OR^(10d),    (CH₂)_(r)SR^(10d), (CH₂)_(r)NR^(10a)R^(10a);-   alternatively, R⁹ and R¹⁰ join to form ═O, a C₃₋₁₀ cycloalkyl, a    5-6-membered lactone or lactam, or a 4-6-membered saturated    heterocycle containing 1-2 heteroatoms selected from O, S, and    NR^(10g) and optionally fused with a benzene ring or a 6-membered    aromatic heterocycle;-   R¹¹, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,    (CR′R¹⁷)_(q)OH, (CH₂)_(q)SH, (CR′R¹⁷)_(q)OR^(11d),    (CH₂)_(q)SR^(11d);-   R¹², is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,    (CHR′)_(q)OH, (CH₂)_(q)SH, (CHR′)_(q)OR^(12d), (CH₂)_(q)SR^(12d),    (CHR′)_(q)NR^(12a)R^(12a); and-   R¹⁴, at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br,    I, F, NO₂, CN, (CHR′)_(r)NR^(14a)R^(14a), (CHR′)_(r)OH,    (CHR′)_(r)O(CHR′)_(r)R^(14d), (CHR′)_(r)SH, (CHR′)_(r)C(O)H,    (CHR′)_(r)S(CHR′)_(r)R^(14d).-   In another embodiment, the present invention provides compounds of    formula (I), wherein ring D is selected from

In another embodiment, the present invention provides compounds offormula (I), wherein Z is selected from O, S, N(CN), and N(CONH₂).

In another embodiment, the present invention provides compounds offormula (I), wherein Z is selected from O, N(CN) and NC(O)NH₂.

In another embodiment, the present invention provides compounds offormula (I), wherein Z is O.

In another embodiment, the present invention provides compounds offormula (I), wherein R¹ and R² are independently selected from H andC₁₋₄ alkyl.

In another embodiment, the present invention provides compounds offormula (I), wherein R¹ and R² are H.

In another embodiment, the present invention provides compounds offormula (I), wherein R¹⁹ is absent, taken with the nitrogen to which itis attached to form an N-oxide, or selected from C₁₋₈ alkyl,(CH₂)_(r)C₃₋₆ cycloalkyl, and (CH₂)_(r)-phenyl substituted with 0-3R^(19c); R^(19c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, (CH₂)_(r)OH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(19a)R⁹, and (CH₂)_(r)phenyl; alternatively, R¹⁹ joins withR⁷, R⁹, or R¹¹ to form a 5, 6 or 7 membered piperidinium spirocycle orpyrrolidinium spirocycle substituted with 0-3 R^(a).

In another embodiment, the present invention provides compounds offormula (I), wherein R¹⁹ is absent.

In another embodiment, the present invention provides compounds offormula (I), wherein R¹³, at each occurrence, is independently selectedfrom C₁₋₄ alkyl, C₃₋₆ cycloalkyl, (CH₂)NR^(13a)R^(13a), (CHR′)OH,(CH₂)OR^(13b), (CH₂)_(w)C(O)R^(13b), (CH₂)_(w)C(O)NR^(13a)R^(13a),(CH₂)NR^(13d)C(O)R^(13a), (CH₂)_(w)S(O)₂NR^(13a)R^(13a),(CH₂)NR^(13d)S(O)₂R^(13b), and (CH₂)w-phenyl substituted with 0-3R^(13c); R^(13a), at each occurrence, is independently selected from H,C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and phenyl substituted with 0-3 R^(13c);R^(13b), at each occurrence, is independently selected from C₁₋₆ alkyl,C₃₋₆ cycloalkyl, and phenyl substituted with 0-3 R^(13c); R^(13c), ateach occurrence, is independently selected from C₁₋₆ alkyl, C₃₋₆cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl,(CH₂)_(r)OH, and (CH₂)_(r)NR^(13d)R^(13d); R^(13d), at each occurrence,is independently selected from H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl.

In another embodiment, the present invention provides compounds offormula (I), wherein E is —(C═O)—(CR⁹R¹⁰)_(v)—(CR¹¹R¹²)—,—(CR⁷R⁸)—(CR⁹R¹⁰)_(v)—(CR¹¹R¹²),

In another embodiment, the present invention provides compounds offormula (I), wherein E is —(CR⁷R⁸)—(CR⁹R¹⁰)_(v)—(CR¹¹R¹²),

In another embodiment, the present invention provides compounds offormula (I), wherein E is —(CR⁷R⁸)—(CR⁹R¹⁰)_(n)—(CR¹¹R¹²).

In another embodiment, the present invention provides compounds offormula (I), wherein E is

In another embodiment, the present invention provides compounds offormula (I), wherein E is (C═O)—(CR⁹R¹⁰)_(v)—(CR¹¹R¹²)—.

In another embodiment, the present invention provides compounds offormula (I), wherein E is

In another embodiment, the present invention provides compounds offormula (I), wherein E is

In another embodiment, the present invention provides compounds offormula (I), wherein R³ is selected from a (CR^(3a)H)_(r)—C₃₋₈carbocyclic residue substituted with 0-5 R¹⁵, wherein the carbocyclicresidue is selected from phenyl, C₃₋₆ cycloalkyl, naphthyl, andadamantyl; and a (CR^(3a)H)_(r)-heterocyclic system substituted with 0-3R¹⁵, wherein the heterocyclic system is selected from pyridinyl,thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl,benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl,isoquinolinyl, imidazolyl, indolyl, indolinyl, indazolyl, isoindolyl,isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl,1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl,pyrazinyl, and pyrimidinyl.

In another embodiment, the present invention provides compounds offormula (I), wherein R³ is selected from a (CR^(3a)H)_(r)—C₃₋₈carbocyclic residue substituted with 0-5 R¹⁵, wherein the carbocyclicresidue is phenyl; and a (CR^(3a)H)_(r)-heterocyclic system substitutedwith 0-3 R¹⁵, wherein the heterocyclic system is selected fromindazolyl, indolinyl, indazolyl, isoindolyl, isothiadiazolyl,isoxazolyl, and thiazolyl.

In another embodiment, the present invention provides compounds offormula (I), wherein R³ is selected from a C₃₋₈ carbocyclic residuesubstituted with 0-5 R¹⁵, wherein the carbocyclic residue is phenyl; anda heterocyclic system substituted with 0-3 R¹⁵, wherein the heterocyclicsystem is selected from indazolyl, indolinyl, indazolyl, isoindolyl,isothiadiazolyl, isoxazolyl, and thiazolyl.

In another embodiment, the present invention provides compounds offormula (I), wherein R⁵ is selected from (CR^(5a)H)_(t)-phenylsubstituted with 0-5 R¹⁶; and a (CR^(5a)H)_(t)-heterocyclic systemsubstituted with 0-3 R¹⁶, wherein the heterocyclic system is selectedfrom pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl,benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl,benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl,indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl,pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl,thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl.

In another embodiment, the present invention provides compounds offormula (I), wherein R⁵ is CH₂phenyl substituted with 0-3 R¹⁶.

In another embodiment, the present invention provides compound offormula (I), wherein B is selected from O and NR¹⁷.

In another embodiment, the present invention provides compounds offormula (I), wherein R¹⁶, at each occurrence, is independently selectedfrom C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, CF₃, Cl, Br, I, F,(CH₂)_(r)NR^(16a)R^(16a), NO₂, CN, OH, (CH₂)_(r)OR^(16d),(CH₂)_(r)C(O)R^(16b), (CH₂)_(r)C(O)NR^(16a)R^(16a),(CH₂)_(r)NR^(16f)C(O)R^(16b), (CH₂)_(r)S(O)_(p)R^(16b),(CH₂)_(r)S(O)₂NR^(16a)R^(16a), (CH₂)_(r)NR^(16f)S(O)₂R^(16b), and(CH₂)_(r)phenyl substituted with 0-3 R^(16e); R^(16a), at eachoccurrence, is independently selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3 R^(16e); R^(16b),at each occurrence, is independently selected from C₁₋₆ alkyl, C₃₋₆cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3 R^(16e); R^(16d),at each occurrence, is independently selected from C₁₋₆ alkyl andphenyl; R^(16e), at each occurrence, is independently selected from C₁₋₆alkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅alkyl; and R^(16f), at each occurrence, is independently selected fromH, and C₁₋₅ alkyl.

In another embodiment, the present invention provides compounds offormula (I), wherein R¹⁶, at each occurrence, is independently selectedfrom Cl, Br, I, F, and CN.

In another embodiment, the present invention provides compounds offormula (I), wherein R⁴ is selected from H and R⁵.

In another embodiment, the present invention provides compounds offormula (I), wherein R¹⁵, at each occurrence, is independently selectedfrom C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, CF₃, Cl, Br, I, F,(CH₂)_(r)NR^(15a)R^(15a), NO₂, CN, OH, (CH₂)_(r)OR^(15d),(CH₂)_(r)C(O)R^(15b), (CH₂)_(r)C(O)NR^(15a)R^(15a),(CH₂)_(r)NR^(15f)C(O)R^(15b), (CH₂)_(r)OC(O)NR^(15a)R^(15a),(CH₂)_(r)NR^(15f)C(O)OR^(15b), (CH₂)_(r)S(O)_(p)R^(15b),(CH₂)_(r)S(O)₂NR^(15a)R^(15a), (CH₂)_(r)NR^(15f)S(O)₂R^(15b),(CH₂)_(r)phenyl substituted with 0-3 R^(15e), and a (CH₂)_(r)-5-6membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(15e); R^(15a), at each occurrence, isindependently selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and(CH₂)_(r)phenyl substituted with 0-3 R^(15e); alternatively, twoR^(15a)s, along with the N to which they are attached, join to form a5-6 membered heterocyclic system containing 1-2 heteroatoms selectedfrom NR^(15g), O, and S and optionally fused with a benzene ring or a6-membered aromatic heterocycle; R^(15b), at each occurrence, isindependently selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and(CH₂)_(r)phenyl substituted with 0-3 R^(15e); R^(15d), at eachoccurrence, is independently selected from C₁₋₆ alkyl and phenyl;R^(15e), at each occurrence, is independently selected from C₁₋₆ alkyl,Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅ alkyl; andR^(15f), at each occurrence, is independently selected from H, and C₁₋₅alkyl.

In another embodiment, the present invention provides compounds offormula (I), wherein R¹⁵, at each occurrence, is independently selectedfrom C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, CF₃, Cl, Br, I, F,NR^(15a)R^(15a), NO₂, CN, OH, OR^(15d), (CH₂)_(r)C(O)R^(15b),C(O)NR^(15a)R^(15a), NR^(15f)C(O)R^(15b), _(r)OC(O)NR^(15a)R^(15a),NR^(15f)C(O)OR^(15b), S(O)_(p)R^(15b), S(O)₂NR^(15a)R^(15a), NR^(15f)S(O)₂R^(15b), (CH₂)_(r)phenyl substituted with 0-3 R^(15e), and a(CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-2 R^(15e), wherein theheterocyclic system is selected from tetrazolyl; R^(15a), at eachoccurrence, is independently selected from H, methyl, ethyl, propyl,isopropy, benzyl and phenyl; R^(15b), at each occurrence, isindependently selected from H, methyl, ethyl, propyl, isopropy, benzyland phenyl; R^(15d), at each occurrence, is independently selected frommethyl, ethyl, propyl, isopropy, and phenyl; R^(15e), at eachoccurrence, is independently selected from C₁₋₆ alkyl, Cl, F, Br, I, CN,NO₂, (CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅ alkyl; and R^(15f), at eachoccurrence, is independently selected from H, and methyl, ethyl, propyland isopropyl.

In another embodiment, the present invention provides compounds offormula (I), wherein A is selected from cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and phenyl.

In another embodiment, the present invention provides compounds offormula (I), wherein A is selected from cyclohexyl, and phenyl.

In another embodiment, the present invention provides compounds offormula (I), wherein A is cyclohexyl.

In another embodiment, the present invention provides compounds offormula (I), wherein R⁹, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, F, Cl, Br, I, NO₂, CN, (CHR′)_(r)OH, (CH₂)_(r)OR^(9d),(CH₂)_(r)SR^(9d), (CH₂)_(r)NR^(9a)R^(9a), (CH₂)_(r)C(O)OH,(CH₂)_(r)C(O)R^(9b), (CH₂)_(r)C(O)NR^(9a)R^(9a),(CH₂)_(r)NR^(9a)C(O)R^(9b), (CH₂)_(r)NR^(9a)C(O)H,C₁₋₆ haloalkyl, a(CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(9c), and a(CH₂)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(9c); R^(9a), at eachoccurrence, is independently selected from H, C₁₋₆ alkyl, C₃₋₈ alkenyl,C₃₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5R^(9e), and a (CH₂)_(r)-4-10 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R^(9e);alternatively, two R⁹ as, along with the N to which they are attached,join to form a 5-6 membered heterocyclic system containing 1-2heteroatoms selected from NR^(9g), O, and S and optionally fused with abenzene ring or a 6-membered aromatic heterocycle.

In another embodiment, the present invention provides compounds offormula (I), wherein R⁹, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(q)OH, (CH₂)_(q)SH, (CH₂)_(q)OR^(9d),(CH₂)_(q)SR^(9d), (CH₂)_(q)NR^(9a)R^(9a).

In another embodiment, the present invention provides compounds offormula (I), wherein R¹⁰, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, F, Cl, Br, I, NO₂, CN, (CHR′)_(r)OH, (CH₂)_(r)OR^(10d),(CH₂)_(r)SR^(10d), (CH₂)_(r)NR^(10a)R^(10a); alternatively, R⁹ and R¹⁰join to form ═O, a C₃₋₁₀ cycloalkyl, a 5-6-membered lactone or lactam,or a 4-6-membered saturated heterocycle containing 1-2 heteroatomsselected from O, S, and NR^(10g) and optionally fused with a benzenering or a 6-membered aromatic heterocycle.

In another embodiment, the present invention provides compounds offormula (I), wherein R¹⁰, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(q)OH, (CH₂)_(q)SH, (CH₂)_(q)OR^(10d),(CH₂)_(q)SR^(10d), (CH₂)_(q)NR^(10a)R^(10a).

In another embodiment, the present invention provides compounds offormula (I), wherein R¹¹, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CR′R¹⁷)_(q)OH, (CH₂)_(q)SH, (CR′R¹⁷)_(q)OR^(11d),(CH₂)_(q)SR^(11d).

In another embodiment, the present invention provides compounds offormula (I), wherein R¹², is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CHR′)_(q)OH, (CH₂)_(q)SH, (CHR′)_(q)OR^(12d),(CH₂)_(q)SR^(12d), (CHR′)_(q)NR^(12a)R^(12a).

In another embodiment, the present invention provides compounds offormula (I), wherein R⁷ is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(q)OH, (CH₂)_(q)SH, (CH₂)_(q)OR^(7d),(CH₂)_(q)SR^(7d), (CH₂)_(q)NR^(7a)R^(7a).

In another embodiment, the present invention provides compounds offormula (I), wherein R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are H.

In another embodiment, the present invention provides compounds offormula (I), wherein q is selected from 1, 2, and 3; and r is selectedfrom 0, 1, 2, and 3.

In another embodiment, the present invention provides compounds offormula (I), wherein r is selected from 0, 1, and 2.

In another embodiment, the present invention provides compounds offormula (I), wherein R¹⁴, at each occurrence, is independently selectedfrom H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆cycloalkyl, Cl, Br, I, F, NO₂, CN, (CHR′)_(r)NR^(14a)R^(14a),(CHR′)_(r)OH, (CHR′)_(r)O(CHR′)_(r)R^(14d), (CHR′)_(r)SH,(CHR′)_(r)C(O)H, (CHR′)_(r)S(CHR′)_(r)R^(14d).

In another embodiment, the present invention provides compounds offormula (I), wherein R¹⁷ is selected from H and methyl.

[15] In another embodiment, the present invention provides compounds offormula (I), wherein the compound is selected from:

-   N-(3-Acetyl-phenyl)-N′-{-3-[(2S)-3-benzyl]-5-oxo-piperazin-1-yl-propyl}-urea.-   N-(5-Acetyl-4-methyl-thiazol-2-yl)-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-(5-Acetyl-4-methyl-thiazol-2-yl)-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-3,6-dioxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-(5-Acetyl-4-methyl-thiazol-2-yl)-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-(2S)-2-hydroxymethyl-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-(5-Acetyl-4-methyl-thiazol-2-yl)-N′{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl-(2R)-2-hydroxymethyl-3-oxo-piperizine-2-yl-methyl)-cyclohexyl}-urea-   N-(5-Acetyl-4-methyl-thiazol-2-yl)-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-3-oxo-4-N-methyl-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-(5-Acetyl-4-methyl-thiazol-2-yl)-N′-{(1R,2S)-2-[(5S)-5-(3-fluoro-benzyl)-3-oxo-4-N-methyl-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-(5-Acetyl-4-methyl-thiazol-2-yl)-N′-{(1R,2S)-2-[(5S)-5-(2-fluoro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-(5-Acetyl-4-methyl-thiazol-2-yl)-N′-{(1R,2S)-2-[(5S)-5-benzyl-3,6-di-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-(5-Acetyl-4-methyl-thiazol-2-yl)-N′-{(1R,2S)-2-[(5S)-5-benzyl-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-(5-Acetyl-4-methyl-thiazol-2-yl)-N′-{(1R,2S)-2-[(5R)-5-(4-fluoro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-(5-Acetyl-4-methyl-thiazol-2-yl)-N′-{(1R,2S)-2-[(5S)-5-(4-chloro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-(5-Acetyl-4-methyl-thiazol-2-yl)-N′-{(1R,2S)-2-[(5R)-5-(4-chloro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-(5-Acetyl-4-methyl-thiazol-2-yl)-N′-{(1R,2S)-2-[(5S)-5-(1-phenyl-ethyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-(5-Acetyl-4-methyl-thiazol-2-yl)-N′-{(1R,2S)-2-[3-oxo-4-N-(4-fluoro-benzyl)-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-phenyl-N′-{(1R,2S)-2-[(5S)-5-benzyl-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-phenyl-N′-{(1R,2S)-2-[(5R)-5-benzyl-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-phenyl-N′-{(1R,2S)-2-[(5S)-5-benzyl-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-cyanoguanidine.-   N-phenyl-N′-{(1R,2S)-2-[3-oxo-4-N-(4-fluoro-benzyl)-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-phenyl-N′-{(1R,2S)-2-[(2S)-2-benzyl-6-oxo-morpholin-4-yl-methyl]-cyclohexyl}-urea.-   N-(3-cyanophenyl)-N′-{(1R,2S)-2-[(5S)-5-benzyl-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-(3-cyanophenyl)-N′-{(1R,2S)-2-[(5S)-5-benzyl-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-cyanoguanidine.    N-(3-Acetyl-4-fluorophenyl)-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-(3-acetylphenyl)-N′-{(1R,    2S)-2-[(5S)-5-benzyl-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-cyanoguanidine.-   N-(3-acetylphenyl)-N′-{(1R,    2S)-2-[(5S)-5-benzyl-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-(3-acetylphenyl)-N′-{(1R,    2S)-2-[(5S)-5-(4-fluoro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-(3-acetylphenyl)-N′-{(1R,2S)-2-[(5S)-5-(3-fluoro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-(3-acetylphenyl)-N′-{(1R,2S)-2-[(5S)-(2-fluoro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-(3-acetylphenyl)-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-(2S)-2-hydroxymethyl-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-(3-acetylphenyl)-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-(2R)-2-hydroxymethyl-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-(3-Acetyl-phenyl)-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-3-oxo-4-N-methyl-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-(3-Acetyl-phenyl)-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-3-oxo-4-N-benzyl-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-(3-Acetyl-phenyl)-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-3,6-di-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-(3-Acetyl-phenyl)-N′-{(1R,2S)-2-[(5R)-5-(4-fluoro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-(3-Acetyl-phenyl)-N′-{(1R,2S)-2-[(5S)-5-(4-chloro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-(3-Acetyl-phenyl)-N′-{(1R,2S)-2-[(5S)-5-(3-cyano-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-(3-Acetyl-phenyl)-N′-{(1R,2S)-2-[(5R)-5-(3-cyano-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-(3-Acetyl-phenyl)-N′-{(1R,2S)-2-[(5S)-5-(1-phenyl-ethyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-(3-Acetyl-phenyl)-N′-{(1R,2S)-2-[3-oxo-4-N-(4-fluoro-benzyl)-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-(3-Acetyl-phenyl)-N′-{(1R,2S)-2-[(2S)-2-(benzyl)-6-oxo-morpholin-4-yl-methyl]-cyclohexyl}-urea.-   N-(3-Acetyl-phenyl)-N′-{(1R,2S)-2-[4-oxo-1,3,4,6,11,11a-hexahydro-pyrazino[1.2-b]-isoquinolin-2-yl-methyl]-cyclohexyl}-urea.-   N-[3-(1-hydroxy-ethyl)-phenyl]-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-(2S)-(2-hydroxy-methyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-(indazol-5-yl)-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-3,6-di-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-(indazol-5-yl)-N′-{(1R,2S)-2-[(5S)-5-benzyl-3,6-di-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-(indazol-5-yl)-N′-{(1R,2S)-2-[(5S)-5-benzyl-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-(indazol-5-yl)-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-(3,5-di-Acetyl-phenyl)-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-(3,5-di-Acetyl-phenyl)-N′-{(1R,2S)-2-[(5S)-5-(3-fluoro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-(3,5-di-Acetyl-phenyl)-N′-{(1R,2S)-2-[(5S)-5-(2-fluoro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-(3,5-di-Acetyl-phenyl)-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-3-oxo-4-N-methyl-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-(3,5-di-Acetyl-phenyl)-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-3,6-di-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-(3,5-di-Acetyl-phenyl)-N′-{(1R,2S)-2-[(5R)-5-(4-fluoro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-(3,5-di-Acetyl-phenyl)-N′-{(1R,2S)-2-[(5S)-5-(1-phenyl-ethyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-(3,5-di-Acetyl-phenyl)-N′-{(1R,2S)-2-[(2S)-2-(benzyl)-6-oxo-morpholin-4-yl-methyl]-cyclohexyl}-urea.-   N-(3,5-di-Acetyl-phenyl)-N′-{(1R,2S)-2-[(5S)-5-(2-fluoro-benzyl)-3,6-di-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-(3,5-di-Acetyl-phenyl)-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-3-oxo-4-N-methyl-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-(3,5-di-Acetyl-phenyl)-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-3-oxo-4-N-benzyl-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-N′-{(1R,2S)-2-[(5S)-5-(2-fluoro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-(2S)-2-hydroxymethyl-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-(2R)-2-hydroxymethyl-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-3-oxo-4-N-methyl-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-3-oxo-4-N-benzyl-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-N′-{(1R,2S)-2-[(5R)-5-(4-fluoro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-N′-{(1R,2S)-2-[(5S)-5-(4-chloro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-N′-{(1R,2S)-2-[(5S)-5-(3-cyano-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-N′-{(1R,2S)-2-[(5R)-5-(3-cyano-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-N′-{(1R,2S)-2-[(5S)-5-(1-phenyl-ethyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-N′-{(1R,2S)-2-[3-oxo-4-N-(4-fluoro-benzyl)-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-)-N′-{(1R,2S)-2-[4-oxo-1,3,4,6,11,11a-hexahydro-pyrazino[1.2-b]-isoquinolin-2-yl-methyl]-cyclohexyl}-urea.-   N-[indolin-5-yl)phenyl]-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-[indolin-5-yl)phenyl]-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-(4-methyl-thiazol-2-yl)-N′-{(1R,2S)-2-[(5S)-5-(3-fluoro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-(thiadiazol-2-yl)-N′-{(1R,    2S)-2-[(5S)-5-(4-fluoro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-(1-methyl-pyrazol-3-yl) —N′-{(1R,    2S)-2-[(5S)-5-(4-fluoro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.-   N-(thiazol-2-yl)-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.

In another embodiment, the present invention provides a pharmaceuticalcomposition, comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of the present invention.

In another embodiment, the present invention provides a method formodulation of chemokine receptor activity comprising administering to apatient in need thereof a therapeutically effective amount of a compoundof the present invention.

In another embodiment, the present invention provides pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of the present inventionor a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method of ofmodulation of chemokine receptor activity which comprises contacting aCCR³ receptor with an effective inhibitory amount of the compound.

In another embodiment, the present invention provides a method fortreating or preventing inflammatory disorders comprising administeringto a patient in need thereof a therapeutically effective amount of acompound of the present invention, or a pharmaceutically acceptable saltthereof.

In another embodiment, the present invention provides a method fortreating or preventing disorders selected from asthma, allergicrhinitis, atopic dermatitis, inflammatory bowel diseases, idiopathicpulmonary fibrosis, bullous pemphigoid, helminthic parasitic infections,allergic colitis, eczema, conjunctivitis, transplantation, familialeosinophilia, eosinophilic cellulitis, eosinophilic pneumonias,eosinophilic fasciitis, eosinophilic gastroenteritis, drug inducedeosinophilia, HIV infection, cystic fibrosis, Churg-Strauss syndrome,lymphoma, Hodgkin's disease, and colonic carcinoma.

In another embodiment, the present invention provides a method fortreating or preventing disorders selected from asthma, allergicrhinitis, atopic dermatitis, and inflammatory bowel diseases.

In another embodiment, the present invention provides a method fortreating or preventing asthma.

In another embodiment, the present invention provides novel compounds offormula (I) for use in therapy.

In another embodiment, the present invention provides the use of novelcompounds of formula (I) for the manufacture of a medicament for thetreatment of HIV infection.

It is understood that any and all embodiments of the present inventionmay be taken in conjunction with any other embodiment to describeadditional embodiments of the present invention. Furthermore, anyelements of an embodiment are meant to be combined with any and allother elements from any of the embodiments to describe additionalembodiments. For example, the first embodiment may be combined with theemobodiment wherein R¹⁹ is absent, taken with the nitrogen to which itis attached to form an N-oxide, or selected from C₁₋₈ alkyl,(CH₂)_(r)C₃₋₆ cycloalkyl, and (CH₂)_(r)-phenyl substituted with 0-3R^(19c); R^(19c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, (CH₂)_(r)OH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(19a)R⁹, and (CH₂)_(r)phenyl; alternatively, R¹⁹ joins withR⁷, R⁹, or R¹¹ to form a 5, 6 or 7 membered piperidinium spirocycle orpyrrolidinium spirocycle substituted with 0-3 R^(a); and furthercombined with the embodiment wherein Z is O. As a further example, theembodiment wherein Z is selected from O, S, N(CN), and N(CONH₂) may becombined with any other embodiment listed above.

Definitions

The compounds herein described may have asymmetric centers. Compounds ofthe present invention containing an asymmetrically substituted atom maybe isolated in optically active or racemic forms. It is well known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis from optically active starting materials.Many geometric isomers of olefins, C═N double bonds, and the like canalso be present in the compounds described herein, and all such stableisomers are contemplated in the present invention. C is and transgeometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. All chiral, diastereomeric, racemic forms and allgeometric isomeric forms of a structure are intended, unless thespecific stereochemistry or isomeric form is specifically indicated.

The term “substituted,” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valency isnot exceeded, and that the substitution results in a stable compound.When a substituent is keto (i.e., ═O), then 2 hydrogens on the atom arereplaced.

When any variable (e.g., R^(a)) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0-2 R^(a), then saidgroup may optionally be substituted with up to two R^(a) groups andR^(a) at each occurrence is selected independently from the definitionof R^(a). Also, combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

As used herein, “C₁₋₈ alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, examples of which include, but are notlimited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,sec-butyl, t-butyl, pentyl, and hexyl. C₁₋₈ alkyl, is intended toinclude C₁, C₂, C₃, C₄, C₅, C₆, C₇, and C₈ alkyl groups. “Alkenyl” isintended to include hydrocarbon chains of either a straight or branchedconfiguration and one or more unsaturated carbon-carbon bonds which mayoccur in any stable point along the chain, such as ethenyl, propenyl,and the like. “Alkynyl” is intended to include hydrocarbon chains ofeither a straight or branched configuration and one or more unsaturatedtriple carbon-carbon bonds which may occur in any stable point along thechain, such as ethynyl, propynyl, and the like. “C₃₋₆ cycloalkyl” isintended to include saturated ring groups having the specified number ofcarbon atoms in the ring, including mono-, bi-, or poly-cyclic ringsystems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, andcycloheptyl in the case of C₇ cycloalkyl. C₃₋₆ cycloalkyl, is intendedto include C₃, C₄, C₅, and C₆ cycloalkyl groups

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, andiodo; and “haloalkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups, for example CF₃,having the specified number of carbon atoms, substituted with 1 or morehalogen (for example —C_(v)F_(w) where v=1 to 3 and w=1 to (2v+1)).

As used herein, the term “5-6-membered cyclic ketal” is intended to mean2,2-disubstituted 1,3-dioxolane or 2,2-disubstituted 1,3-dioxane andtheir derivatives.

As used herein, “carbocycle” or “carbocyclic residue” is intended tomean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7,8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic, any of which maybe saturated, partially unsaturated, or aromatic. Examples of suchcarbocycles include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,;[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane(decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl,adamantyl, or tetrahydronaphthyl (tetralin).

As used herein, the term “heterocycle” or “heterocyclic system” isintended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or7, 8, 9,, or 10-membered bicyclic heterocyclic ring which is saturated,partially unsaturated or unsaturated (aromatic), and which consists ofcarbon atoms and 1, 2, 3, or 4 heteroatoms independently selected fromthe group consisting of N, NH, O and S and including any bicyclic groupin which any of the above-defined heterocyclic rings is fused to abenzene ring. The nitrogen and sulfur heteroatoms may optionally beoxidized. The heterocyclic ring may be attached to its pendant group atany heteroatom or carbon atom which results in a stable structure. Theheterocyclic rings described herein may be substituted on carbon or on anitrogen atom if the resulting compound is stable. If specificallynoted, a nitrogen in the heterocycle may optionally be quaternized. Itis preferred that when the total number of S and O atoms in theheterocycle exceeds 1, then these heteroatoms are not adjacent to oneanother. As used herein, the term “aromatic heterocyclic system” isintended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7-to 10-membered bicyclic heterocyclic aromatic ring which consists ofcarbon atoms and from 1 to 4 heteroatoms independently selected from thegroup consisting of N, O and S.

Examples of heterocycles include, but are not limited to, 1H-indazole,2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl,4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,carbazolyl, 4aH-carbazolyl, β-carbolinyl, chromanyl, chromenyl,cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl,isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl,isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl,oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl., oxazolyl, oxazolidinylperimidinyl,phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl,purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl,pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, tetrazolyl, and xanthenyl. Preferred heterocyclesinclude, but are not limited to, pyridinyl, thiophenyl, furanyl,indazolyl, benzothiazolyl, benzimidazolyl, benzothiaphenyl,benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl,imidazolyl, indolyl, isoidolyl, piperidinyl, piperidonyl, 4-piperidonyl,piperonyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl,thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl. Also included are fusedring and spiro compounds containing, for example, the aboveheterocycles.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418, the disclosure of which is hereby incorporated byreference.

Since prodrugs are known to enhance numerous desirable qualities ofpharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.. . . ) the compounds of the present invention may be delivered inprodrug form. Thus, the present invention is intended to cover prodrugsof the presently claimed compounds, methods of delivering the same andcompositions containing the same. “Prodrugs” are intended to include anycovalently bonded carriers which release an active parent drug of thepresent invention in vivo when such prodrug is administered to amammalian subject. Prodrugs the present invention are prepared bymodifying functional groups present in the compound in such a way thatthe modifications are cleaved, either in routine manipulation or invivo, to the parent compound. Prodrugs include compounds of the presentinvention wherein a hydroxy, amino, or sulfhydryl group is bonded to anygroup that, when the prodrug of the present invention is administered toa mammalian subject, it cleaves to form a free hydroxyl, free amino, orfree sulfhydryl group, respectively. Examples of prodrugs include, butare not limited to, acetate, formate and benzoate derivatives of alcoholand amine functional groups in the compounds of the present invention.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. Only stable compounds are envisioned forthis invention.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention alone or an amount of the combinationof compounds claimed or an amount of a compound of the present inventionin combination with other active ingredients effective to treat theinflammatory diseases described herein.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)preventing the disease-state from occurring in a mammal, in particular,when such mammal is predisposed to the disease-state but has not yetbeen diagnosed as having it; (b) inhibiting the disease-state, i.e.,arresting it development; and/or (c) relieving the disease-state, i.e.,causing regression of the disease state.

Synthesis

The compounds of Formula I can be prepared using the reactions andtechniques described below. The reactions are performed in a solventappropriate to the reagents and materials employed and suitable for thetransformations being effected. It will be understood by those skilledin the art of organic synthesis that the functionality present on themolecule should be consistent with the transformations proposed. Thiswill sometimes require a judgment to modify the order of the syntheticsteps or to select one particular process scheme over another in orderto obtain a desired compound of the invention. It will also berecognized that another major consideration in the planning of anysynthetic route in this field is the judicious choice of the protectinggroup used for protection of the reactive functional groups present inthe compounds described in this invention. An authoritative accountdescribing the many alternatives to the trained practitioner is Greeneand Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991).

Generally, the route described in Scheme 1 can be used to synthesize thecompounds described in the scope of this patent application. Theappropriately substituted piperazin-2-one (B=N—R¹⁷) 1 or morpholin-2-one(B=O) 1 is alkylated by a N-protected alkylhalide (halide=Cl, Br, I),mesylate, tosylate or triflate) 2 to yield the 4-alkyl-piperazin-2-oneor morpholin-2-one protected amine 3. (In the following schemes,substituents on ring D are designated as R⁵, R⁶, and R¹³. Thisdesignation is for the purposes of the Schemes only and is not meant tolimit the definitions for ring D substitution in the claims.) Erepresents a linkage described within the scope of this application inits fully elaborated form (or in a precursor form which can be laterelaborated) with the appropriate protecting groups as understood by oneskilled in the art. If the halide is not I, then KI can also be added tofacilitate the displacement, provided the solvent is suitable, such asan alcohol, 2-butanone, DMF or DMSO, amongst others. The displacementcan be performed at room temperature to the reflux temperature of thesolvent. Alternatively, the appropriately substituted piperazin-2-one 1or morpholin-2-one 1 is reductively alkylated with the aldehyde 2(X=CHO), to give the protected amine 3. The protecting group issubsequently removed to yield amine 4. Suitable protected amino groupsinclude: phthalimide (which can be removed by hydrazine); bis-BOC (whichcan be removed by either TFA or HCl dissolved in a suitable solvent); anitro group (instead of an amine which can be reduced to yield anamine); 2,4-dimethylpyrrole (S. P. Breukelman, et al. J. Chem. Soc.Perkin Trans. 1,1984, 2801);N-1,1,4,4-Tetramethyl-disilylazacyclopentane (STABASE) (S. Djuric, J.Venit, and P. Magnus Tet. Lett 1981, 22, 1787); and other protectinggroups know by one skilled in the art. Reaction with an isocyanate orisothiocyanate 5 (Z=O,S) yields urea or thiourea 6. Reaction with achloroformate or chlorothioformate 7 (Z=O,S) such as o-,p-nitrophenyl-chloroformate or phenylchloroformate (or theirthiocarbonyl equivalents), followed by diplacement with an amine 9, alsoyields the corresponding urea or thiourea 6. Likewise, reaction ofcarbamate 8 (Y=H, or 2- or 4-NO2) with disubstituted amine 10 yieldstrisubstituted urea or thiourea 12. Reaction of the amine 4 with anN,N-disubstituted carbamoyl chloride 11 (or its thiocarbonyl equivalent)yields the corresponding N,N-disubstituted urea or thiourea 12. Amine 4can also be reductively aminated to yield 13 by conditions familiar toone skilled in the art and by the following conditions: Abdel-Magid, A.F., et al. Tet. Lett. 1990, 31, (39) 5595-5598. This secondary amine cansubsequently be reacted with isocyanates or isothiocyanates to yieldtrisubstituted ureas 14 or with carbamoyl chlorides to yieldtetrasubstituted ureas 15.

One can also convert amine 4 into an isocyanate, isothiocyanate,carbamoyl chloride or its thiocarbonyl equivalent (isocyanate:Nowakowski, J. J Prakt. Chem/Chem-Ztg 1996, 338 (7), 667-671; Knoelker,H.-J. et al., Angew. Chem. 1995, 107 (22), 2746-2749; Nowick, J. S. etal., J. Org. Chem. 1996, 61 (11), 3929-3934; Staab, H. A.; Benz, W.;Angew Chem 1961, 73; isothiocyanate: Strekowski L. et al., J.Heterocycl. Chem. 1996, 33 (6), 1685-1688; Kutschy, Pet al., Synlett.1997, (3), 289-290) carbamoyl chloride: Hintze, F.; Hoppe, D.; Synthesis(1992) 12, 1216-1218; thiocarbamoyl chloride: Ried, W.; Hillenbrand, H.;Oertel, G.; Justus Liebigs Ann Chem 1954, 590) (these reactions are notshown in Scheme 1). These isocyanates, isothiocyantes, carbamoylchlorides or thiocarbamoyl chlorides can then be reacted with R²R³NH toyield di- or trisubstituted ureas or thioureas 12. An additional ureaforming reaction involves the reaction of carbonyldiimidazole (CDI)(Romine, J. L.; Martin, S. W.; Meanwell, N. A.; Epperson, J. R.;Synthesis 1994 (8), 846-850) with 4 followed by reaction of theintermediate imidazolide with 9 or in the reversed sequence (9+CDI,followed by 4). Activation of imidazolide intermediates also facilitatesurea formation (Bailey, R. A., et al., Tet. Lett. 1998, 39, 6267-6270).One can also use 13 and 10 with CDI. The urea forming reactions are donein a non-hydroxylic inert solvent such as THF, toluene, DMF, etc., atroom temperature to the reflux temperature of the solvent and can employthe use of an acid scavenger or base when necessary such as carbonateand bicarbonate salts, triethylamine, DBU, Hunigs base, DMAP, etc.

Substituted piperazin-2-ones 1 can either be obtained commercially or beprepared as shown in Scheme 2. Commercially available N-protected aminoacids can be converted to the Weinreb amides 17, which are then reducedwith LAH to the aldehydes 18 (R⁵=H) or treated with Grignards to givethe ketones 18. Reductive amination of 18 with benzyl amines or aminoesters 20 gives the amines 19 or 21, respectively. Alkylation of 19 withester 23 (X=halide, mesylate, triflate, etc.) gives the ester 22.Removal of the nitrogen protecting group of 21 or 22, followed bycyclization gives the piperazin-2-ones 25 or 24. The amide nitrogen ofpiperazin-2-ones 24 can be alkylated (NaH, R^(17X)) to give 27.Hydrogenolysis of 27 gives the desired piperazin-2-ones 28.Alternatively, the basic nitrogen of piperazin-2-ones 25 can bealkylated to give the isomeric piperazin-2-ones 26.

The corresponding substituted morpholin-2-one (B=O) 1 can prepared asshown in Scheme 3. Commercially available N-protected amino acids can beconverted to the Weinreb amides 17, which are then reduced with LAH tothe aldehydes 18 (R⁶=H) or treated with Grignards to give the ketones18. Reduction of 18 gives the amino alcohols 31 (B=O). Alternately, theα-hydroxy acid derivatives can be converted to the Weinreb amides 29,which can then reduced with LAH to the aldehydes 30 (R⁵=H) or treatedwith Grignards to give the ketones 30. Reductive amination of 30 givesthe amines 31 (B=O). Reductive amination of 30 with amino esters 20 oralkylation of 31 (B=O) with ester 23 (X=halide, mesylate, triflate,etc.) gives the ester 33. Removal of the oxygen protecting group of 33,followed by cyclization gives the morpholin-2-ones 34. The amino ketone18 can be reduced to the alcohol 31 (B=O) or can under go a reductiveamination to the diamine 31 (B=N—R¹⁷). These can also be acylated withthe α-hydroxy acid derivative 36 to give the amide 32. Removal of theprotecting group of 32, followed by cyclization gives the isomericmorpholin-3-ones or piperazin-3-ones 35.

Compounds where Z=N—CN, CHNO₂, and C(CN)₂ can be synthesized by themethods shown in Scheme 4. Amine 10 (Scheme 1) reacts with malononitrile37 neat or in an inert solvent at room temperature to the refluxtemperature of the solvent, or at the melting point of the solid/solidmixture, to yield maloonitrile 38. Likewise, a similar reaction sequencemay be used to make 40 and 42. These in turn can undergo reaction withamine 4 under similar conditions stated just above to yield thederivative 15. The malononitrile analog (Z=C(CN)₂) may be synthesized bythe method of S. Sasho, et al. (J. Med. Chem. 1993, 36, 572-579, and P.Traxler, et al., J. Med. Chem. (1997), 40, 3601-3616. Thecyanoguanidines (Z=N—CN) can be synthesized by the method of K. S.Atwal, et al. and references contained

therein (J. Med. Chem. (1998) 41, 271-275). The nitroethylene analog(Z=C—NO₂) can be synthesized by the method of F. Moimas, et al.(Synthesis 1985, 509-510) and J. M. Hoffman, et al., (J. Med. Chem.(1983) 26, 140-144) and references contained therein.

Guanidines (Z=NR^(1a)) can be synthesized by the methods outlined inScheme 5. Compound 43 where Z=S can be methylated to yield themethylisothiourea 44. Displacement of the SMe group with amines yieldssubstituted guanidines 45 (see H. King and I. M. Tonkin J. Chem. Soc.1946, 1063 and references therein). Alternatively, reaction of thiourea43 with amines in the presence of triethanolamine and “lac sulfur” whichfacilitates the removal of H₂S yields substituted guanidines 45 (K.Ramadas, Tet. Lett. 1996, 37, 5161 and references therein).

A method for introducing substituents in linkage E is that of A. Chesneyet al. (Syn. Comm. 1990, 20 (20), 3167-3180) as shown in Scheme 6.Michael reaction of piperazin-2-one (B=N—R¹⁷) 1 or morpholin-2-one (B=O)1 with Michael acceptor 46 yields intermediate 47 which can undergosubsequent reactions in the same pot. For example, reduction yieldsalcohol 48 which can be elaborated to the amine 49 by standardprocedures familiar to one skilled in the art. Some of these includemesylation or tosylation followed by displacement with NaN₃ followed byreduction to yield amine 49. Another route as depicted in Scheme 6involves reaction with diphenylphosphoryl azide followed by reduction ofthe azide to yield amine 49.

The mesylate or tosylate can also be displaced by other nucleophilessuch as NH₃, BOC₂N⁻, potassium phthalimide, etc., with subsequentdeprotection where necessary to yield amines 49. Finally, 49 can beconverted to urea or thiourea 50 by procedures discussed for Scheme 1 orto the compounds of this invention by procedures previously discussed.Similarly, aldehyde 47 may be reacted with a lithium or a Grignardreagent 51 to yield alcohol adduct 52. This in turn can be converted tourea or thiourea 54 in the same way as discussed for the conversion of48 to 50.

Scheme 7 shows that intermediate 56 can be extended via a Wittigreaction (A. Chesney, et al. Syn. Comm. 1990, 20 (20), 3167-3180) toyield 57. This adduct can be reduced catalytically to yield 58 or byother procedures familiar to one skilled in the art. Alkylation yields59, followed by saponification and Curtius rearrangement (T. L. Capsonand C. D. Poulter, Tet. Lett., (1984) 25, 3515-3518) followed byreduction of the benzyl protecting group yields amine 60 which can beelaborated further as was described earlier in Scheme 1 and elsewhere inthis application to make the compounds of this invention.

Scheme 8 shows that dialkyllithium cuprate, organocopper, orcopper-catalyzed Grignard addition (for a review, see G. H. Posner, “AnIntroduction to Synthesis Using Organocopper Reagents”, J. Wiley, NewYork, 1980; Organic Reactions, 19, 1 (1972)) to alpha,beta-unsaturatedester 57 yields 61 which can undergo subsequent transformations justdiscussed to yield amine 63, and then elaborated further to thecompounds of this invention as was described earlier. The intermediateenolate ion obtained upon cuprate addition to 57 can also be trapped byan electrophile to yield 62 (for a review, see R. J. K. Taylor,Synthesis 1985, 364). Likewise, another 2-carbon homologation isreported by A. Chesney et al. (ibid.) on intermediate 56 which involvesreacting 56 with an enolate anion to yield aldol condensation product 62(where R¹⁰=OH). The hydroxyl group can undergo synthetic transformationswhich are familiar to one skilled in the art and which will be discussedin much detail later on in the application. Chiral auxilliaries can alsobe used to introduce stereo- and enantioselectivity in these aldolcondensations, procedures familiar to one skilled in the art. Examplesof such methods are taught in D. A. Evans, et al., J. Am. Chem. Soc.1981, 103, 2127; D. A. Evans, J. Am. Chem.Soc. 1982, 104, 1737; D. A.Evans, J. Am. Chem. Soc. 1986, 108, 2476; D. A. Evans. et al., J. Am.Chem. Soc. 1986, 108, 6757; D. A. Evans, J. Am. Chem. Soc. 1986, 108,6395; D. A. Evans, J. Am. Chem. Soc. 1985, 107, 4346; A. G. Myers, etal., J. Am. Chem. Soc. 1997, 119, 6496. One can also perform anenantioselective alkylation on esters 58 or 61 with R¹²X where X is aleaving group as described in Scheme 1, provided the ester is firstattached to a chiral auxiliary (see above references of Evans, Myers andMauricio de L. Vanderlei, J. et al., Synth. Commum. 1998, 28, 3047).

One can also react alpha,beta-unsaturated ester 57 (Scheme 9) withCorey's dimethyloxosulfonium methylide (E. J. Corey and M. Chaykovsky,J. Am. Chem. Soc. 1965, 87, 1345) to form a cyclopropane which canundergo eventual Curtius rearrangement and subsequent elaboration to thecompounds of this invention wherein the carbon containing R⁹R¹⁰ is tiedup in a cyclopropane ring with the carbon containing R¹¹R¹².

In addition, compound 68 (Scheme 9a) can also undergo the analogousreactions just described to form cyclopropylamine 70, which can befurther elaborated into the compounds of this invention as describedpreviously. Compound 68 can also be synthesized by an alkylationreaction of piperazin-2-one 1 or morpholin-2-one 1 with bromide 67 in aninert solvent employing the conditions as described for the alkylationof 2 by 1 in Scheme 1.

Another way to synthesize the compounds in the scope of this applicationis shown in Scheme 10. Michael reaction of amine 1 with an acrylonitrile71 (as described by I. Roufos in J. Med. Chem. 1996, 39, 1514-1520)followed by Raney-Nickel hydrogenation yields amine 73 which can beelaborated to the compounds of this invention as previously described.

In Schemes 6,7, and 10, we see that there is no gem-substitution on thealpha-carbon to the electron-withdrawing group of what used to be theMichael acceptor. In other words, in Scheme 6, there is no R¹⁰ gem toR⁹; in Scheme 7, there is no R¹⁰ gem to one of the R^(9s) and in Scheme10 there is no R¹⁰ gem to R⁹. Gem-substitution can be introduced byreacting piperazin-2-one or morpholin-2-one 1 with the epoxide ofMichael acceptors 46, 55, and 71 to yield the corresponding alcohols(for amines reacting with epoxides of Michael acceptors, see Charvillon,F. B.; Amouroux, R.; Tet. Lett. 1996, 37, 5103-5106; Chong, J. M.;Sharpless, K. B.; J Org Chem 1985, 50, 1560). These alcohols eventuallycan be further elaborated into R¹⁰ by one skilled in the art, as, forexample, by tosylation of the alcohol and cuprate displacement(Hanessian, S.; Thavonekham, B.; DeHoff, B.; J. Org. Chem. 1989, 54,5831), etc., and by other displacement reactions which will be discussedin great detail later on in this application.

Further use of epoxides to synthesize compounds of this invention areshown in Scheme 11. Reaction of piperazin-2-one or morpholin-2-one 1with epoxide 74 yields protected amino-alcohol 75. This reaction worksexceptionaly well when R⁷ and R⁸ are H but is not limited thereto. Thereaction is performed in an inert solvent at room temperature to thereflux temperature of the solvent. Protecting groups on the nitrogenatom of 74 include BOC and CBZ but are not limited thereto. The hydroxylgroup can be optionally protected by a variety of protecting groupsfamiliar to one skilled in the art. Deprotection of the nitrogen gives76 which can be elaborated to the compounds of this invention by theprocedures previously discussed.

If R⁹=H, then oxidation, for example, by using PCC (Corey E. J. andSuggs, J. W., Tet. Lett. 1975, 31, 2647-2650) or with the Dess-Martinperiodinane (Dess, D. B. and Martin, J. C., J. Org. Chem. 1983, 48,4155-4156) yields ketone 77. Ketone 77 may undergo nucleophilic1,2-addition with organometallic reagents such as alkyl- oraryllithiums, Grignards, or zinc reagents, with or without CeCl₃ (T.Imamoto, et al., Tet. Lett. 1985, 26, 4763-4766; T. Imamoto, et al.,Tet. Lett. 1984, 25, 4233-4236) in aprotic solvents such as ether,dioxane, or THF to yield alcohol 78. The hydroxyl group can beoptionally protected by a variety of protecting groups familiar to oneskilled in the art. Deprotection of the nitrogen yields 76 which can befinally elaborated to the compounds of this invention as previouslydiscussed. Epoxides disclosed by structure 74 may be synthesizedenantio-selectively from amino acid starting materials by the methods ofDellaria, et al. J Med Chem 1987, 30 (11), 2137, and Luly, et al. J OrgChem 1987, 52 (8), 1487.

The carbonyl group of ketone 77 in Scheme 11 may undergo Wittigreactions followed by reduction of the double bond to yield alkyl,arylalkyl, heterocyclic-alkyl, cycloalkyl, cycloalkylalkyl, etc.substitution at that position, reactions that are familiar to oneskilled in the art. Wittig reagents can also contain functional groupswhich after reduction of the double bond yield the followingfunctionality: esters (Buddrus, J. Angew Chem., 1968, 80), nitrites(Cativiela, C. et al., Tetrahedron 1996, 52 (16), 5881-5888.), ketone(Stork, G. et al., J Am Chem Soc 1996, 118 (43), 10660-10661), aldehydeand methoxymethyl (Bertram, G. et al., Tetrahedron Lett 1996, 37 (44),7955-7958.), gamma-butyrolactone Vidari, G. et al., Tetrahedron:Asymmetry 1996, 7 (10), 3009-3020.), carboxylic acids (Svoboda, J. etal., Collect Czech Chem Commun 1996, 61 (10), 1509-1519), ethers(Hamada, Y. et al., Tetrahedron Lett 1984, 25 (47), 5413), alcohols(after hydrogenation and deprotection—Schonauer, K.; Zbiral, E.;Tetrahedron Lett 1983, 24 (6), 573), amines (Marxer, A.; Leutert, T.Helv Chim Acta, 1978, 61) etc., all of which may further undergotransformations familiar to one skilled in the art to form a widevariety of functionality at this position.

Scheme 12 summarizes the displacement chemistry and subsequentelaborations that can be used to synthesize the R⁹ groups. In Scheme 12we see that alcohol 75 or 78 may be tosylated, mesylated, triflated, orconverted to a halogen by methods familiar to one skilled in the art toproduce compound 79. (Note that all of the following reactions in thisparagraph can be also performed on the compounds, henceforth calledcarbon homologs of 75 or 78 where OH can be (CH₂)_(r)OH and it is alsounderstood that these carbon homologs may have substituents on themethylene groups as well). For example, a hydroxyl group may beconverted to a bromide by CBr₄ and Ph₃P (Takano, S. Heterocycles 1991,32, 1587). For other methods of converting an alcohol to a bromide or toa chloride or to an iodide see R. C. Larock, Comprehensive OrganicTransformations, VCH Publishers, New York, 1989, pp. 354-360. Compound79 in turn may be displaced by a wide variety of nucleophiles as shownin Scheme 12 including but not limited to azide, cyano, malonate,cuprates, potassium thioacetate, thiols, amines, etc., all nucleophilicdisplacement reactions being familiar to one skilled in the art.Tosylate 79 can undergo displacement with cuprates to yield 85(Hanessian, S.; Thavonekham, B.; DeHoff, B.; J. Org. Chem. 1989, 54,5831). Halide, mesylate, tosylate or triflate 79 can undergodisplacement with azide followed by reduction to yield amine 84 aprocedure familiar to one skilled in the art. Displacement by malonateyields malonic ester 83. Displacement by nitrile yields a one-carbonhomologation product 80. Nitrile 80 can be reduced with DIBAL to yieldaldehyde 81. This aldehyde can undergo reduction to alcohol 82 with, forexample, NaBH4 which in turn can undergo all of the SN₂ displacementreactions mentioned for alcohol 75 or 78.

Alcohol 75 or 78, 82, or 97, can be acylated by procedures familiar toone skilled in the art, for example, by Schotten-Baumann conditions withan acid chloride or by an anhydride with a base such as pyridine toyield 86. Alcohol 82 is a one carbon homolog of alcohol 75 or 78. Thusone can envision taking alcohol 82, converting it to a leaving group Xas discussed above for compound 75 or 78, and reacting it with NaCN orKCN to form a nitrile, subsequent DIBAL reduction to the aldehyde andsubsequent NaBH₄ reduction to the alcohol resulting in a two carbonhomologation product. This alcohol can undergo activation followed bythe same SN₂ displacement reactions discussed previously, ad infinitum,to result in 3,4,5 . . . etc. carbon homologation products.

Alcohols may be converted to the corresponding fluoride 87 by DAST(diethylaminosulfur trifluoride) (Middleton, W. J.; Bingham, E. M.; Org.Synth. 1988, VI, pg. 835). Sulfides 88 can be converted to thecorresponding sulfoxides 89 (p=1) by sodium metaperiodate oxidation (N.J. Leonard, C. R. Johnson J. Org. Chem. 1962, 27, 282-4) and to sulfones89 (p=2) by Oxone® (A. Castro, T. A. Spencer J. Org. Chem. 1992, 57,3496-9). Sulfones 89 can be converted to the corresponding sulfonamides90 by the method of H.-C. Huang, E. et al., Tet. Lett. (1994) 35,7201-7204 which involves first, treatment with base followed by reactionwith a trialkylborane yielding a sulfinic acid salt which can be reactedwith hydroxylamine-O-sulfonic acid to yield a sulfonamide. Another routeto sulfonamides involves reaction of amines with a sulfonyl chloride (G.Hilgetag and A. Martini, Preparative Organic Chemistry, New York: JohnWiley and Sons, 1972, p.679). This sulfonyl chloride (not shown inScheme 12) can be obtained from the corresponding sulfide (88 whereR^(9d)=H in Scheme 12, the hydrolysis product after thioacetatedisplacement), disulfide, or isothiouronium salt by simply reacting withchlorine in water. The isothiouronium salt may be synthesized from thecorresponding halide, mesylate or tosylate 79 via reaction with thiourea(for a discussion on the synthesis of sulfonyl chlorides see G. Hilgetagand A. Martini, ibid., p. 670).

As shown in Scheme 13 Aldehyde 81 can also be reacted with a lithium orGrignard reagent to form an alcohol 91 which can also undergo the abovedisplacement reactions. Oxidation by methods familiar to one skilled inthe art yields ketone 92. Malonic ester 83 can be saponified anddecarboxylated to yield carboxylic acid 93, a two carbon homologationproduct. Conversion to ester 94 (A. Hassner and V. Alexanian, Tet. Lett,1978, 46, 4475-8) and reduction with LAH yields alcohol 97 which canundergo all of the displacement reactions discussed for alcohol 75 or78.

Carboxylic acid 93 can be converted to amides 95 by standard couplingprocedures or via an acid chloride by Schotten-Baumann chemistry or to aWeinreb amide (95: R^(9a)=OMe, R^(9a)=Me in Scheme 13) (S. Nahm and S.M. Weinreb, Tet. Lett., 1981, 22, 3815-3818) which can undergo reductionto an aldehyde 96 (R^(9b)=H in Scheme 13) with LAH (S. Nahm and S. M.Weinreb, ibid.) or reactions with Grignard reagents to form ketones 96(S. Nahm and S. M. Weinreb, ibid.). The aldehyde 96 obtained from theWeinreb amide reduction can be reduced to the alcohol with NaBH₄. Thealdehyde or ketone 96 (or 81 or 92 for that matter) can undergo Wittigreactions as discussed previously followed by optional catalytichydrogenation of the olefin. This Wittig sequence is one method forsynthesizing the carbocyclic and heterocyclic substituted systems at R⁹employing the appropriate carbocyclic or heterocyclic Wittig (orHorner-Emmons) reagents. Of course, the Wittig reaction may also be usedto synthesize alkenes at R⁹ and other functionality as well. Ester 94can also form amides 95 by the method of Weinreb (A. Basha, M. Lipton,and S.M. Weinreb, Tet. Lett. 1977, 48, 4171-74) (J. I. Levin, E. Turos,S. M. Weinreb, Syn. Comm. 1982, 12, 989-993). Alcohol 97 can beconverted to ether 98 by procedures familiar to one skilled in the art,for example, NaH, followed by an alkyliodide or by Mitsunobu chemistry(Mitsunobu, O. Synthesis, 1981, 1-28). Amine 84 can again undergooptional reductive amination followed by reaction with a sulfonylchloride to yield 100, for example under Schotten-Baumann conditions asdiscussed previously. This amine can undergo optional reductiveamination and acylation to yield 99 or reaction with ethyl formate(usually refluxing ethyl formate) to yield formamide 99. This samesequence may be employed for amine obtained from the reduction ofnitrile 80.

Aldehyde 81 or its homologous extensions can be reacted with a carbonanion of an aryl (phenyl, naphthalene, etc.) or heterocyclic group toyield an aryl alcohol or a heterocyclic alcohol. If necessary, CeCl₃ maybe added (T. Imamoto, et al., Tet. Lett. 1985, 26, 4763-4766; T.Imamoto, et al., Tet. Lett. 1984, 25, 4233-4236). This alcohol may bereduced with Et₃SiH and TFA (J. Org. Chem. 1969, 34, 4; J. Org. Chem.1987, 52, 2226). These aryl and heterocyclic anions may also bealkylated by 79 (or its carbon homolog) to yield compounds where R⁹contains an aryl or heterocyclic group. Compound 79 or its carbonhomologs may be alkylated by an alkyne anion to produce alkynes at R⁹(see R. C. Larock, Comprehensive Organic Transformations, New York,1989, VCH Publishers, p 297). In addition, carboxaldehyde 81 or itscarbon homologs can undergo 1,2-addition by an alkyne anion (Johnson, A.W. The Chemistry of Acetylenic Compounds. V. 1. “Acetylenic Alcohols,”Edward Arnold and Co., London (1946)). Nitro groups can be introduced bydisplacing bromide 79 (or its carbon homologs) with sodium nitrite inDMF (J. K. Stille and E. D. Vessel J. Org. Chem. 1960, 25, 478-490) orby the action of silver nitrite on iodide 79 or its carbon homologs(Org. Syntheses 34, 37-39).

If an anion is made of the piperazin-2-one or morpholin-2-one 1 with LDAor n-BuLi, etc., then that anion in a suitable nonhydroxylic solventsuch as THF, ether, dioxane, etc., can react in a Michael-type fashion(1,4-addition) with an alpha,beta-unsaturated ester to yield anintermediate enolate which can be quenched with an electrophile (R⁹X)(where X is as described in Scheme 1) (Uyehara, T.; Asao, N.; Yamamoto,Y.; J Chem Soc, Chem Commun 1987, 1410) as shown in Scheme 14.

It is to be understood that R⁹ is either in its final form or in asuitable protected precursor form. This electrophile can be acarbon-based electrophile, some examples being formaldehyde to introducea CH₂OH group, an aldehyde or a ketone which also introduces aone-carbon homologated alcohol, ethylene oxide (or other epoxides) whichintroduces a —CH₂CH₂OH group (a two-carbon homologated alcohol), analkyl halide, etc., all of which can be later elaborated into R⁹.

It can also be an oxygen-based electrophile such as MCPBA, Davis'reagent (Davis, F. A.; Haque, M. S.; J Org Chem 1986, 51 (21),4083;Davis, F. A.; Vishwaskarma, L. C.; Billmers, J. M.; Finn, J.; J Org Chem1984, 49, 3241) or MoO₅ (Martin, T. et al., J Org Chem 1996, 61 (18),6450-6453) which introduces an OH group. These OH groups can undergo thedisplacement reactions discussed previously in Scheme 12 or protected bysuitable protecting groups and deprotected at a later stage when thedisplacement reactions decribed in Scheme 12 can be performed. Inaddition, these hydroxyl groups can also undergo displacement reactionsto introduce N- or C-substituted heterocycles at this position.

Ester 102 can be converted into its Weinreb amide 104 (S. Nahm and S. M.Weinreb, Tet. Lett., 1981, 22, 3815-3818) or Weinreb amide 104 can besynthesized via Michael-type addition of 1 to alpha,beta-unsaturatedWeinreb amide 105. Subsequent reaction with a Grignard reagent formsketone 107. This ketone can also be synthesized in one step directlyfrom the piperazin-2-one or morpholin-2-one 1 and alpha,beta-unsaturatedketone 106 using the same procedure. This ketone may be reduced withLAH, NaBH₄ or other reducing agents to form alcohol 108. Or else, ketone107 can be reacted with an organolithium or Grignard reagents to formtertiary alcohol 109. Or else, ester 102 can be directly reduced withLiBH4 or LAH to yield primary alcohol 110.

Alcohols 108, 109, and 110 can all be tosylated, mesylated, triflated,or converted to a halogen by methods discussed previously and displacedwith an amine nucleophile such as azide, diphenylphosphoryl azide (withor without DEAD and Ph₃P), phthalimide, etc. as discussed previously(and which are familiar to one skilled in the art) and after reduction(azide) or deprotection with hydrazine (phthalimide), for example, yieldthe corresponding amines. These can then be elaborated into thecompounds of this invention as discussed previously.

Ketone 107 can also be converted into imine 111 which can be reactedwith a Grignard reagent or lithium reagent, etc., to form a protectedamine 112 which can be deprotected and elaborated into the compounds ofthis invention as discussed previously. Some protecting groups includebenzyl, substituted benzyls, which can be removed by hydrogenation, andcyanoethyl, which can be removed with aqueous base, etc. It is to beunderstood that R⁷⁻¹² in Scheme 10 can be in their final form or inprecursor form which can be elaborated into final form by proceduresfamiliar to one skilled in the art.

Magnesium amides of amines have been used to add in a Michael-typemanner to alpha,beta-unsaturated esters where the substituents at thebeta position of the unsaturated ester are tied together to form acyclopentane ring (for example, compound 101 where R⁷ and R⁸ are takentogether to be —(CH₂)₄—) (Kobayashi, K. et al., Bull Chem Soc Jpn, 1997,70 (7), 1697-1699). Thus reaction of piperazin-2-one or morpholin-2-one1 with cycloalkylidine esters 101 as in Scheme 14 yields esters 102where R⁷ and R⁸ are taken together to form a cycloalkyl ring. Subsequentelaboration yields compounds of this invention where R⁷ and R⁸ are takentogether to form a cycloalkyl ring.

Compounds of structure 118 may also be synthesized from epoxyalcohols asshown in Scheme 15. Allylic alcohol 113 can be epoxidized eitherstereoselectively using VO(acac)₂ catalyst (for a review, see Evans:Chem. Rev. 1993, 93, 1307) or enantioselectively (Sharpless: J. Am.Chem. Soc. 1987, 109, 5765) to epoxyalcohol 114. S_(N)2 displacement ofthe alcohol using zinc azide and triphenylphosphine (Yoshida, A. J. Org.Chem. 57, 1992, 1321-1322) or diphenylphosphoryl azide, DEAD, andtriphenylphosphine (Saito, A. et al., Tet. Lett. 1997, 38 (22),3955-3958) yields azidoalcohol 115. Hydrogenation over a Pd catalystyields aminoalcohol 116. This can be protected in situ or in asubsequent step with BOC₂O to put on a BOC protecting group, or withCBZ-Cl and base to put on a CBZ-group or other protecting groups.Alternatively, the amino group can be reacted with an isocyanate, anisothiocyanate, a carbamoyl chloride, or any reagent depicted in Scheme1 to form 117, which can be alkylated with 1 to form the compounds ofthis invention.

Sometimes the epoxide ring have to be activated with Lewis acids inorder for the piperazin-2-one or morpholin-2-one 1 to open the ring(Fujiwara, M.; Imada, M.; Baba, A.; Matsuda, H.;Tetrahedron Lett 1989,30, 739; Caron, M.; Sharpless, K. B.; J Org Chem 1985, 50, 1557) or 1has to be deprotonated and used as a metal amide, for example thelithium amide (Gorzynski-Smith, J.; Synthesis 1984 (8), 629) or MgBramide (Carre, M. C.; Houmounou, J. P.; Caubere, P.; Tetrahedron Lett1985, 26, 3107) or aluminum amide (Overman, L. E.; Flippin, L. A.;Tetrahedron Lett 1981, 22, 195).

The quaternary salts (R¹⁹ is a substituent) of piperazin-2-one ormorpholin-2-one can be synthesized by simply reacting the amine with analkylating agent. Suitable alkylating agent are methyl iodide, methylbromide, ethyl iodide, ethyl bromide, ethyl or methyl bromoacetate,bromoacetonitrile, allyl iodide, allylbromide, benzyl bromide, etc.Suitable solvents for these reactions include THF, DMF, DMSO, etc. andcan be carried our at room temperature to the reflux temperature of thesolvent.

Spiroquaternary salts, such as 119, 121, 123, or 125 can be synthesizedin a similar manner, the only difference being that the alkylating agentis located intramolecularly as shown in Scheme 16. It is understood byone skilled in the art that functional groups might not be in theirfinal form to permit cyclization to the quaternary ammonium salt andmight have to be in precursor form or in protected form to be elaboratedto their final form at a later stage. For example, the NR¹(C=Z)NR²R³group on the rightmost phenyl ring of compound 124 might exist as anitro group precursor for ease of manipulation during quaternary saltformation. Subsequent reduction and NR¹(C=Z)NR²R³ group formation yieldsproduct 125. The leaving groups represented by X in Scheme 16 may equalthose represented in Scheme 1, but are not limited thereto. N-oxides ofpiperazin-2-one or morpholin-2-one can be made by the procedure of L. W.Deady (Syn. Comm. 1977, 7, 509-514). This simply entails reacting thepiperazin-2-one or morpholin-2-one with MCPBA, for example, in an inertsolvent such as methylene chloride.

Compounds where R⁹ and R¹⁰ form a cyclic 3,4,5,6, or 7-membered ring canbe synthesized by the methods disclosed in Scheme 17. These same methodsmay also be used to synthesize gem-disubstituted compounds in which R⁹can be different from R¹⁰ by step-wise alkylation of the malonatederivative. Of course, this scheme may also be used to synthesizecompounds where R¹⁰=H. For example, a cyclohexyl-fused malonate may besynthesized by Michael addition and alkylation of I(CH₂)₄CH═CCO₂Me withdimethyl malonate employing NaH/DMF (Desmaele, D.; Louvet, J.-M.; TetLett 1994, 35 (16), 2549-2552) or by a double Michael addition (Reddy,D. B., et al., Org. Prep. Proced. Int. 24 (1992) 1, 21-26) or by analkylation followed by a second intromolecular alkylation employing aniodoaldehyde (Suami, T.; Tadano, K.; Kameda, Y.; Iimura, Y.; Chem Lett1984, 1919), or by an alkylation followed by a second intramolecularalkylation employing an alkyl dihalide (Kohnz, H.; Dull, B.; Mullen, K.;Angew Chem 1989, 101 (10), 1375), etc.

Subsequent monosaponification (Pallai, P. V., Richman, S., Struthers, R.S., Goodman, M. Int. J. Peptide Protein Res. 1983, 21, 84-92; M. GoodmanInt. J. Peptide Protein Res. 19831, 17, 72-88), standard coupling withpiperazin-2-one or morpholin-2-one 1 yields 128. Reduction with boraneyields 129 followed by reduction with LAH yields 130 which can be thenconverted to amine 131 and then to the compounds of this invention byprocedures as discussed previously. Ester 129 can also be converted to aWeinreb amide and elaborated to the compounds of this invention asdescribed in Scheme 14 for ester 102 which would introduce substituentsR¹¹ and R¹².

Scheme 18 describes another method for the synthesis of compounds whereR⁹ and R¹⁰ are taken together to form cycloalkyl groups. Amino alcohols132 are found in the literature (CAS Registry Nos. for n=0,1,2,3,respectively: 45434-02-4, 2041-56-7, 2239-31-8, 2041-57-8). They caneasily be protected, as with a BOC group (or CBZ, or any othercompatible protecting group) by known procedures familiar to one skilledin the art to yield alcohols 133. The alcohols can then be activated byconversion to a halide (or to a mesylate, tosylate or triflate bymethods discussed previously), and then alkylated with piperazin-2-one(B=N—R¹⁷) or morpholin-2-one (B=O) 1 as described in Scheme 1 to yield135. Subsequent deprotection yields amine 136, which can be elaboratedto the compounds of this invention as described previously.

Of course, alcohol 133 can be oxidized to the aldehyde and then reactedwith R^(7or8)MgBr or R^(7or8)Li with or without CeCl₃ to yield thecorresponding alcohol 133 where instead of —CH₂OH, we would have—CHR^(7or8)OH. This oxidation-1,2-addition sequence may be repeated toyield a tertiary alcohol. The alcohol may then be tosylated, mesylated,triflated, or converted to Cl, Br, or I to yield 134 and then displacedwith piperazin-2-one or morpholin-2-one 1 to yield 135. Subsequentdeprotection yields 136, which may undergo elaboration to the compoundsof this invention as discussed previously. The aldehyde derived from 133can also undergo reductive amination with 1 to give 135.

A method to introduce cycloalkyl groups at R¹¹R¹² is shown in Scheme 19.Protection of the nitrogen of compounds 137, which are commerciallyavailable, yields 138 (the protecting group may be BOC, CBZ, or anyother compatible protecting group) by procedures familiar to one skilledin the art. Esterification by any one of a number procedures familiar toone skilled in the art (for example A. Hassner and V. Alexanian, Tet.Lett, 1978, 46, 4475-8) followed by reduction with DIBAL (oralternatively reduction to the alcohol with, for example, LiBH4,followed by Swern oxidation (op. cit.)) yields aldehyde 139. One carbonhomologation via the Wittig reaction followed by hydrolysis of the vinylether yields aldehyde 141. Reductive amination (Abdel-Magid, A. F., etal. Tet. Lett. 1990, 31, (39) 5595-5598) yields 142 followed bydeprotection yields amine 143

which can be elaborated to the compounds of this invention by themethods previously discussed. Of course, aldehyde 139 can be reactedwith R^(9or10)MgBr or R^(9or10)Li with or without CeCl3 to yield analcohol that can be oxidized to a ketone. Wittig one-carbon homologationon this ketone as described above followed by hydrolysis yields 141where the —CH₂CHO is substituted with one R^(9or10) group (—CHR^(9or10)CHO). Aldehyde 141 (—CH₂CHO) or its monosubstituted analog synthesizedabove (—CHR^(9or10)CHO) can undergo alkylation with R^(9or10)X where Xis as defined in Scheme 1 to yield compound

141 containing one or both of the R⁹ and R¹⁰ substituents alpha to thealdehyde group. Alkylation can be performed using LDA or lithiumbistrimethylsilyl amide amongst other bases in an inert solvent such asether, THF, etc., at −78° C. to room temperature. Aldehyde 141(—CH₂CHO)or its substituted analogs synthesized above (i.e.,—CHR⁹R¹⁰CHO) can undergo reductive amination with 1 and subsequentelaboration to the compounds of this invention. Aldehyde 141 (—CH₂CHO)orits substituted analogs synthesized above (i.e., —CHR⁹R¹⁰CHO) can alsoundergo 1,2-addition with R^(7or8)MgBr or R^(7or8)Li to yield thecorresponding alcohol —CH₂CHR^(7or8)OH or —CHR⁹R¹⁰CHR^(7or8)OH. Thealcohol may then be tosylated, mesylated, triflated, or converted to Cl,Br, or I by procedures familiar to one skilled in the art and displacedwith piperazin-2-one or morpholin-2-one 1 to yield, after subsequentdeprotection and elaboration, the compounds of this invention. Or elsealcohol —CH₂CHR^(7or8)OH or —CR⁹R¹⁰CHR^(7or8)OH can be oxidized (i.e.,Swern, op. cit.) to the ketone and reductively aminated with 1 andsubsequently elaborated to the compounds of this invention. Or elsealcohol —CH₂CHR^(7or8)OH or —CR⁹R¹⁰CHR^(7or8)OH can be oxidized (i.e.,Swern, op. cit.) to the ketone and reacted once more with R^(7or8)MgBror R^(7or8)Li to yield the corresponding alcohol —CH₂CR⁷R⁸OH or—CR⁹R¹⁰CR⁷R⁸OH. If the ketone enolizes easily, CeCl₃ may be usedtogether with the Grignard or lithium reagent. The alcohol can again betosylated, mesylated, triflated, or converted to Cl, Br, or I byprocedures familiar to one skilled in the art and displaced withpiperazin-2-one or morpholin-2-one 1 to yield, after subsequentdeprotection and elaboration, the compounds of this invention. Thus eachone of the R⁷, R⁸, R⁹, and R¹⁰ groups may be introduced into compounds141, 142 and 143 and, of course, in the compounds of this invention, bythe methods discussed above.

The compounds of the present invention in which E contains ring A can beprepared in a number of ways well known to one skilled in the art oforganic synthesis. As shown in Scheme 20, reductive amination ofaldehyde 148 with mono-protected diamine 147 gives the diprotectedtriamine 149. The diamine 147 can be synthesized from the a-amino acidsvia their Weinreb amides 144 as shown in Scheme 20. The Weinreb amide(144: in Scheme 20) (S. Nahm and S. M. Weinreb, Tet. Lett., 1981, 22,3815-3818) can undergo reduction to an aldehyde 145 (R⁶=H in Scheme 20)with LAH (S. Nahm and S. M. Weinreb, ibid.) or reactions with

Grignard reagents to form ketones 145 (S. Nahm and S. M. Weinreb,ibid.). Reductive amination of the ketone gives the mono-protecteddiamine 147. The synthesis of 148 can be accomplish from thecorresponding known amino acid or amino alcohol (J. Org. Chem. 1996, 61,5557-63; J. Am. Chem. Soc. 1996, 118, 5502-03). The free amine of 149can then be acylated with the acyl bromide 36 to give the α-bromo amide150. Removal of the amino protecting group and cyclization gives thepiperazin-3-one 151. Scheme 20 also highlights the synthesis of theisomeric piperazin-3-one instead of the piperazin-2-one that has beenexemplified in the previous schemes.

Another method to synthesize the isomeric piperazin-3-ones as well asthe isomeric morpholin-3-one analogs (see also 35 in Scheme 3) is shownin Scheme 21. Reductive amination of 148 with amino alcohol 31 gives152. The free amine is then coupled with the α-amino or α-hydroxy acidderivative 153 to give the amide 154. Conversion of the free hydroxylgroup to a good leaving group, removal of the protecting group ona-amino or α-hydroxy amide, and cyclization gives the isomericpiperazin-3-ones or morpholin-3-one analogs 155.

The corresponding diketo-piperazine and diketo-morpholines can also besynthesized using a similar strategy outlined in Scheme 22. Reductiveamination of 148 with an α-amino acid ester 20 gives the amino ester153. This can be coupled with a second α-amino acid or an α-hydroxy acid153 to give the amide ester 157. Removal of the α-protecting group andcyclization gives the diketo analog 158. Subsequent removal of the aminoprotecting group of 158 (as well as 155 and 151) gives the free aminewhich can be elaborated further to compounds of this invention asdescribed in earlier schemes.

Synthesis of examples that incorporate a phenyl group as the carbocyclein linkage E is shown in the next few schemes. Scheme 23 shows the useof a benzyl alkylating agent 159 (X=Br,Cl, mesylate, tosylate, triflate,etc) with piperazin-2-one or morpholin-2-one 1 give the N-benzylcompound 160. The nitro group of 160 is then reduced using catalytichydrogenation to give the corresponding aniline 161. The aniline aminogroup can then be elaborated further to compounds of this invention asdescribed in earlier schemes.

As shown in Scheme 24, piperazin-2-one or morpholin-2-one 1 can also beN-alkylated with the phenacyl bromide 162 to give the nitro ketone 163.The nitro group of 163 is then reduced using catalytic hydrogenation togive the corresponding aniline 164. The ketone of 164 can be reducedwith NaBH₄ to give the alcohol 165. Alternatively, the epoxide 166 canbe opened with the piperazin-2-one or morpholin-2-one 1 to give thecorresponding nitro benzyl alcohol, which is hydrogenated to give theaniline alcohol 165 directly. The amino group of aniline 164 and 165 canthen be elaborated further to compounds of this invention as describedin earlier schemes.

The piperazin-2-one or morpholin-2-one 1 can also be N-alkylated with3-cyanobenzyl bromide (167, Scheme 25) to give the cyano analog 168. Thecyano group is reduced using Raney nickel to give the correspondingbenzyl amine 169. The amino group of 169 can then be elaborated furtherto compounds of this invention 170 as described in earlier schemes.

As shown in Scheme 26, 3-cyano aniline can be converted to the urea,thiourea, or other urea isostere as described in previous schemes togive 171. Treatment with HCl/ethanol then converts the cyano group of171 to the imidate 172. Reaction with piperazin-2-one or morpholin-2-one1 with the imidate 172 in ethanol then gives the amidine 173.

Other methods of synthesizing amidines (compounds where R⁷ and R⁸ aretaken together to form ═NR^(8b)) are shown in Scheme 27. Reaction of thepiperazin-2-one or morpholin-2-one 1 with nitrile 173 in the presence ofCuCl catalysis forms amidine 174 where R^(8b) is H (Rousselet, G.;Capdevielle, P.; Maumy, M.; Tetrahedron Lett. 1993, 34 (40), 6395-6398).Note that the urea portion may be in final form or in precursor form(for example, a protected nitrogen atom; P=protecting group such asSTABASE, bis-BOC, etc., as was discussed previously) which may besubsequently elaborated into the compounds of this invention. Compounds174 may be also synthesized by reacting iminoyl chloride 175 withpiperazin-2-one or morpholin-2-one 1 to yield 174 where R^(8b) is not H(Povazanec, F., et al., J. J. Heterocycl. Chem., 1992, 29, 6,1507-1512). Iminoyl chlorides are readily available from thecorresponding amide via PCl₅ or CCl₄/PPh₃ (Duncia, J. V. et al., J. Org.Chem., 1991, 56, 2395-2400). Again, the urea portion may be in finalform or in precursor form.

Syntheses of amines 9, 10, and the amines which are precursors toisocyanates or isothiocyanates 5 will now be discussed. Many amines arecommercially available and can be used as 9, 10, or used as precursorsto isocyanates or isothiocyanates 5. There are numerous methods for thesynthesis of non-commercially available amines familiar to one skilledin the art. For example, aldehydes and ketones may be converted to theirO-benzyl oximes and then reduced with LAH to form an amine (Yamazaki,S.; Ukaji, Y.; Navasaka, K.; Bull Chem Soc Jpn 1986, 59, 525). Ketonesand trifluoromethylketones undergo reductive amination in the presenceof TiCl₄ followed by NaCNBH4 to yield amines (Barney, C. L., Huber, E.W., McCarthy, J. R. Tet. Lett. 1990, 31, 5547-5550). Aldehydes andketones undergo reductive amination with Na(AcO)₃BH as mentionedpreviously to yield amines (Abdel-Magid, A. F., et al. Tet. Lett. 1990,31, (39) 5595-5598). Amines may also be synthesized from aromatic andheterocyclic OH groups (for example, phenols) via the Smilesrearrangement (Weidner, J. J., Peet, N. P. J. Het. Chem., 1997, 34,1857-1860). Azide and nitrile displacements of halides, tosylates,mesylates, triflates, etc. followed by LAH or other types or reductionmethods yield amines. Sodium diformyl amide (Yinglin, H., Hongwen, H.Synthesis 1989 122), potassium phthalimide, and bis-BOC-amine anion canall displace halides, tosylates, mesylates, etc., followed by standarddeprotection methods to yield amines, procedures which are familiar toone skilled in the art. Other methods to synthesize more elaborateamines involve the Pictet-Spengler reaction, imine/immonium ionDiels-Alder reaction (Larsen, S.D.; Grieco, P. A. J. Am. Chem. Soc.1985, 107, 1768-69; Grieco, P. A., et al., J. Org. Chem. 1988, 53,3658-3662; Cabral, J. Laszlo, P. Tet. Lett. 1989, 30, 7237-7238; amidereduction (with LAH or diborane, for example), organometallic additionto imines (Bocoum, A. et al., J. Chem. Soc. Chem. Comm. 1993, 1542-4).

There are many other syntheses of amines like 9 and 10, which are knownin the literature. For example, 3-nitrobenzeneboronic acid 176, which iscommercially available, and can undergo Suzuki couplings (Suzuki, A.Pure Appl. Chem. 1991, 63, 419) with a wide variety of substituted iodo-or bromo aryls (aryls such as phenyl, naphthalene, etc.), heterocycles,alkyls, akenyls (Moreno-manas, M., et al., J. Org. Chem., 1995, 60,2396), or alkynes (154, Scheme 28). It can also undergo coupling withtriflates of aryls, heterocycles, etc. (Fu, J.-m, Snieckus, V. Tet.Lett. 1990, 31, 1665-1668). Both of the above reactions can also undergocarbonyl insertion in the presence of an atmosphere of carbon monoxide(Ishiyama, et al., Tet. Lett. 1993, 34, 7595). These nitro-containingcompounds (178 and 180) can then be reduced to the corresponding amineseither via catalytic hydrogenation, or via a number of chemical methodssuch as Zn/CaCl₂ (Sawicki, E. J Org Chem 1956, 21). The carbonylinsertion compounds (181) can also undergo reduction of the carbonylgroup to either the CHOH or CH₂ linkages by methods already discussed(NaBH₄ or Et₃SiH, TFA, etc.). These amines can then be converted toisocyanate 5 via the following methods (Nowakowski, J. J PraktChem/Chem-Ztg 1996, 338 (7), 667-671; Knoelker, H.-J. et al., Angew Chem1995, 107 (22), 2746-2749; Nowick, J. S. et al., J Org Chem 1996, 61(11), 3929-3934; Staab, H. A.; Benz, W.; Angew Chem 1961, 73); toisothiocyanate 5 via the following methods (Strekowski L. et al., JHeterocycl Chem 1996, 33 (6), 1685-1688; Kutschy, Pet al., Synlett 1997,(3), 289-290); to carbamoyl chloride 11 (after 179 or 181 is reductivelyaminated with an R² group) (Hintze, F.; Hoppe, D.; Synthesis (1992) 12,1216-1218); to thiocarbamoyl chloride 11 (after 179 or 181 isreductively aminated with an R² group) (Ried, W.; Hillenbrand, H.;Oertel, G.; Justus Liebigs Ann Chem 1954, 590); or just used as 9, or 10(after 179 or 181 is reductively aminated with an R² group), insynthesizing the compounds of this invention by the methods depicted inScheme 1.

Likewise, protected aminobromobenzenes or triflates or protectedaminobromoheterocycles or triflates 182 (Scheme 29) may undergoSuzuki-type couplings with arylboronic acids or heterocyclic boronicacids (183). These same bromides or triflates 182 may also undergoStille-type coupling (Echavarren, A. M., Stille, J. K. J. Am. Chem.Soc., 1987, 109, 5478-5486) with aryl, vinyl, or heterocyclic stannanes186. Bromides or triflates 182 may also undergo Negishi-type couplingwith other aryl or heterocyclic bromides 187 (Negishi E. Accts. Chem.Res. 1982, 15, 340; M. Sletzinger, et al., Tet. Lett. 1985, 26, 2951).Deprotection of the amino group yields an amine with can be coupled tomake a urea and other linkers containing Z as described above and forScheme 1. Amino protecting groups include phthalimide,2,4-dimethylpyrrole (S. P. Breukelman, et al. J. Chem. Soc. PerkinTrans. I, 1984, 2801); N-1,1,4,4-Tetramethyldisilyl-azacyclopentane(STABASE) (S. Djuric, J. Venit, and P. Magnus Tet. Lett 1981, 22, 1787)and others familiar to one skilled in the art.

EXAMPLES

The compounds of this invention and their preparation can be understoodfurther by the following working examples. These examples are meant tobe illustrative of the present invention, and are not to be taken aslimiting thereof.

Example 1 (6S)-6-(4-Fluoro-benzyl)-piperazin-2-one.

Part 1.[(1S)-2-(4-Fluoro-phenyl)-1-(methoxy-methyl-carbamoyl)-ethyl]-carbamicacid tert-butyl ester.

A solution of N-Boc 4-fluorophenylalanine (10.0 g, 35 mmol) in THF (100ml) was cooled in an ice bath under an inert atmosphere and treated withN-methylmorphline (4.0 g, 40 mmol). To the cold reaction solution wasadded, dropwise while stirring, isobutylchloroformate (4.8 g, 35 mmol).The mixture was stirred for a few minutes and then treated with asuspension of N,O-dimethyl hydroxylamine HCl (4.0 g, 40 mmol) in DMF.The resulting suspension was stirred for 20 minutes in the ice bath andthen diluted with 500 ml of water and extracted into EtOAc. The organicextract was washed successively with 1N NaOH, 1N HCl, water, and brine.The extract was dried over MgSO₄, filtered and concentrated in vacuo togive 11.4 grams of the desired Weinreb amide as a thick colorless oil.This was sufficiently clean that it was used without furtherpurification. ¹H NMR (300 MHz, CDCl₃) δ 7.26-7.10 (m, 2H), 6.99-6.93 (m,2H), 5.18 (bd, J=8 Hz, 1H), 4.91 (m, 1H), 3.68 (s, 3H), 3.16 (s, 3H),3.06-2.99 (dd, J=7 Hz, J=13 Hz, 1H), 2.88-2.81 (dd, J=7 Hz, J=13 Hz,1H), 1.39 (s, 9H).Part 2. [(1S)-1-(4-Fluoro-benzyl)-2-oxo-ethyl]-carbamic acid tert-butylester.

A solution of the crude amide from part 1 (11.4 g, 35 mmol) in ether(200 ml) was cooled to 0° C. in an ice bath and slowly treatedportion-wise, with solid LAH (1.66 g, 43 mmol). The resulting suspensionwas stirred at 0° C. for 30 minutes. The reaction was quenched bydrop-wise addition of a saturated aqueous solution of KHSO₄ (300 ml).The layers separated and the organic extract washed with 1 N HCl, water,and brine. The extract was dried over MgSO₄, filtered and concentratedon a rotary evaporator to give 9.1 grams of the aldehyde as a whitesolid of sufficient purity that it was used without furtherpurification. ¹H NMR (300 MHz, CDCl₃) δ 9.63 (s, 1H), 7.16-7.11 (m, 2H),6.99-6.95 (m, 2H), 5.08 (bm, 1H), 4.20 (m, 1H), 3.10 (m, 2H), 1.43 (s,3H).Part 3.[(1S)-1-(4-Fluoro-benzyl)-2-((1R)-1-phenyl-ethylamino)-ethyl]-carbamicacid tert-butyl ester.

A solution of crude aldehyde from part 2 above (5.0 g, 18 mmol) inCH₂Cl₂ (100 ml) was treated with R-α-methylbenzyl amine (2.43 g, 20mmol) and Na(OAc)₃BH. The resulting mixture was stirred at roomtemperature for 3 hours (until reaction was complete by TLC). Themixture was quenched with 1N NaOH (50 ml) and stirred for 30 minutes.The organic layer separated and washed with water, and brine. Theextract was dried over MgSO₄, filtered and concentrated on a rotaryevaporator to give a thick oil. This was chromatographed on silica gel(50% EtOAc/Hexane) to give 6.0 grams of diamine product as an oil. ¹HNMR (300 MHz, CDCl₃) δ 7.33-7.20 (m, 5H), 7.09-7.01 (m, 2 h), 6.98-6.88(m, 2H), 4.63 (bm, 1H), 3.89 (bm, 1H), 3.70 (q, 1H), 2.80-2.74 (bm, 1H),2.64-2.52 (m, 3H), 2.37-2.31 (dd, J=7 Hz, J=12 Hz, 1H), 1.42 (s, 9H),1.32 (d, J=7 Hz, 3H). ESI MS: (M+H)⁺=373.2.Part 4.[[(2S)-2-tert-Butoxycarbonylamino-3-(4-fluoro-phenyl)-propyl]-((1R)-1-phenyl-ethyl)-amino]-aceticacid methy ester.

A solution of the diamine from part 3 above (6.0 g, 16 mmol) in DMF (50ml) was treated with methyl bromoacetate (3.7 g, 24 mmol) and K₂CO₃(2.25 g, 16 mmol) and the resulting mixture stirred overnight at roomtemperature. The reaction mixture was diluted with 300 ml of water andextracted into EtOAc. The organic extracts were washed with water, andbrine. The extract was dried over MgSO₄, filtered and concentrated on arotary evaporator to give a thick oil that was used without furtherpurification.Part 5. 6-(4-Fluoro-benzyl)-4-(1-phenyl-ethyl)-piperazin-2-one.

A solution of crude ester from part 4 above (7.1 g, 16 mmol) wasdissolved in 60 ml of CH₂Cl₂ and treated with 75 ml of TFA. The solutionwas stirred at room temperature for 1 hour. The solvent was removed on arotary evaporator to give a thick syrup. This syrup was dissolved inmethanol (200 ml) and neutralized with 1N NaOH. The solution was stirredfor 10 minutes and then diluted with water and extracted into EtOAc. Theorganic extracts were washed with water, and brine. The extract wasdried over MgSO₄, filtered and concentrated on a rotary evaporator togive 4.3 g of a white solid. This was chromatographed on silica gel(50-70% EtOAc/Hexane) to give 2.6 grams of the piperazin-2-one. ¹H NMR(300 MHz, CDCl₃) δ 7.36-7.26 (m, 5H), 7.07-6.92 (m, 4H), 5.90 (bs, 1H),3.58-3.5-(m, 1H), 3.45 (q, J=7 Hz, 1H), 3,28 (d, J=17 Hz, 1H), 3.08 (d,J=17 Hz, 1H), 2.77-2.73 (m, 2H), 2.69-2.64 (dd, J=6 Hz, J=12 Hz, 1H),2.45-2.39 (dd, J=6 Hz, J=15 Hz, 1H), 1.40 (d, J=7 Hz, 1).Part 6. (6S)-6-(4-Fluoro-benzyl)-piperazin-2-one.

A solution of 4-benzyl-piperazin-2-one from part 5 (2.6 g, 8.3 mmol) inmethanol (200 ml) was treated with 1 g of 10% Pd(OH)₂/C and hydrogenatedat 60 psi of hydrogen for 15 hours. The mixture is filtered and thesolvent on a rotary evaporator to give 1.7 grams of the piperazinone asa white solid. [α]_(D) ²⁵=+27.7° (CH₃OH, c=0.354 g/dL). ¹H NMR (300 MHz,CDCl₃) δ 7.17-7.13 (m, 2H), 7.05-6.99 (m, 2H), 6.05 (bs, 1H), 3.70-3.62(m, 1H), 3.57-4,31 (dd, J=17 Hz, J=22 Hz, 2H), 3.18-3.12 (dd, J=6 Hz,J=13 Hz, 1H), 2.87-2.81 (dd, J=6 Hz, J=14 Hz, 1H), 2.75-2.64 (overlapdd, 2H), 1.90 (bs, 1H).

Example 2 (1R,2R)-(2-Formyl-cyclohexyl)-carbamic acid benzyl ester

Step 1: (1R,2R)-(2-Hydroxymethyl-cyclohexyl)-carbamic acid benzyl ester.

To a solution of (1R,2R)-(2-Amino-cyclohexyl)-methanol [J. Am. Chem.Soc. 1996, 118, 5502-5503 and references therein] (1.9 g, 14.7 mmol) inCH₂Cl₂ (50 mL) is added 50 ml of an aqueous solution of Na₂CO₃ (2.4 g,28.9 mmol). While stirring, benzyl chloroformate (2.51 g, 14.7 mmol) isadded and the mixture is stirred at room temperature for 1 hour. Theorganic layer is separated and washed with water and brine. The solutionis concentrated on a rotary evaporator and the residue ischromatographed on silica gel (30% ethyl acetate/hexane) to give 3.1 g(12 mmol) of the N-Cbz amino alcohol as a white solid. ¹H NMR (300 MHz,CDCl₃) δ 7.40-7.29 (m, 5H), 5.11 (s, 2H), 4.71 (bd, 1H), 3.76-3.71 (m,1H), 3.53-3.28 (m, 3H), 2.00-1.95 (m, 1H), 1.90-1.09 (m, 8H). MS AP⁺(M+H)⁺=264.3 (100%)Step 2: (1R,2R)-(2-Formyl-cyclohexyl)-carbamic acid benzyl ester.

A solution of DMSO (2.52 g, 30 mmol) in CH₂Cl₂ (50 mL) is cooled to −78°C. To this solution is added drop-wise oxalyl chloride (1.81 g, 14 mmol)and the resulting solution is stirred for an additional 10 min. Then asolution of N-CBZ amino alcohol from part 1 above (2.5 g, 9.5 mmol) inCH₂Cl₂ (70 ml) is added via an addition funnel and stirred for 10 min.Then Et₃N (5.0 g, 50 mmol) is added and the solution is allowed to warmto room temperature. The solution is diluted with water and the organiclayer washed with water, 1 N HCl, and brine. The organic layer is driedover Na₂SO₄, filtered, and concentrated to give 2.5 g (9.5 mmol) of thealdehyde as a white solid. ¹H NMR (300 MHz, CDCl₃) δ 9.59 (d, 3.6 Hz,1H), 7.38-7.28 (m, 5H), 5.07 (m, 2H), 4.69 (m, 1H), 3.84 (m, 21H),2.19-2.11 (m,1H), 2.09-2.01 (m, 1H), 1.86-1.75 (m, 3H), 1.54-1.17 (m,4H).

Example 34-((1R,2R)-2-Amino-cyclohexylmethyl)-(6S)-6-(4-fluoro-benzyl)-piperazin-2-one.

Part 1.{(1R,2S)-2-[(3S)-3-(4-Fluoro-benzyl)-5-oxo-piperazin-1-ylmethyl]-cyclohexyl}-carbamicacid benzyl ester.

A solution of cyclohexyl aldehyde from EXAMPLE 2 above (2.2 g, 8.4 mmol)and piperazinone from EXAMPLE 1 above (1.7 g, 8.2 mmol) in CH₂Cl₂ (50ml) was treated with Na(OAc)₃BH (2.68 g, 12.6 mmol). The resultingmixture was stirred at room temperature for 4 hours (until reaction wasjudged to be complete by TLC). The mixture was quenched with 1N NaOH (50ml) and stirred for 30 minutes. The organic layer separated and washedwith water, and brine. The extract was dried over MgSO₄, filtered andconcentrated on a rotary evaporator to give a thick oil. This waschromatographed on silica gel (70% EtOAc/Hexane) to give 3.5 grams ofproduct as a white solid. ¹H NMR (300 MHz, CDCl₃) δ 7.36-7.29 (m, 5H),7.03-6.93 (m, 4H), 5.81 (bs, 1H), 5.67 (bs, 1H), 5.09 (bs, 2H), 3.60(bm, 1H), 3,25-3.20 (m, 1H), 3.17 (d, J=16 Hz, 1H), 3.01 (d, J=16 Hz,1H), 2.83-2.51 (m, 5H), 2.40-2.22 (m, 1H), 2.29-2.16 (m, 2H), 1.85-1.81(m, 1H), 1.74-1.70 (m, 2H), 1.39-0.96 (m, 5H).Part 2.4-((1R,2R)-2-Amino-cyclohexylmethyl)-(6S)-6-(4-fluoro-benzyl)-piperazin-2-one.

A solution of N-CBZ cyclohexyl piperazinone from part 1 above (3.5 g,7.7 mmol) in methanol (200 ml) was treated with 2 g of 10% Pd/C andhydrogenated at 60 psi of hydrogen for 15 hours. The mixture is filteredand the solvent removed on a rotary evaporator to give 2.0 grams of thefree amino cyclohexyl piperazinone as a white solid. ¹H NMR (300 MHz,CDCl₃) δ 7.19-7.14 (m, 3H), 7.04-6.98 (m, 2H), 6.05 (bs, 1H), 3.84 (bm,2H), 3.74 (m, 1H), 3.46 (d, J=16 Hz, 1H), 2.84 (d, J=16 Hz, 1H),2.83-2.71 (m, 2H), 2.57 (m, 2H), 2.33 (m, 2H), 1.93 (m, 1H), 1.71 (m,3H), 1.47 (m, 1H), 1.23 (m, 3H), 0.88 (m, 2H).

Example 4 (6S)-6-benzyl-piperazin-2-one

Part 1. (2-Benzyloxycarbonylamino-3-phenyl-propylamino)-acetic acidmethyl ester.

A solution of glycine methyl ester hydrochloride (2.0 g, 15 mmol) inCH₂Cl₂ was treated with triethylamine (1.5 g, 15 mmol).N-Cbz-Phenylalinal (2.0 g, 7.06 mmol) [synthesized following the sameprocedure described above for Example 1 (Part 1 and 2)] and was added tothe resulting solution. Then Na(OAc)₃BH was added and the resultingmixture was stirred at room temperature for 4 hours (until reaction wascomplete by TLC). The mixture was quenched with 1N NaOH (50 ml) andstirred for 30 minutes. The organic layer separated and washed withwater, and brine. The extract was dried over MgSO₄, filtered andconcentrated on a rotary evaporator to give crude diamine.Part 2. (6S)-6-benzyl-piperazin-2-one.

The above crude diamine (1.9 g, 5.3 mmol) was dissolved in methanol andtreated with 10% Pd/C and hydrogenated at 50 psi of hydrogen overnight.The mixture is filtered and the solvent removed on a rotary evaporatorto give 0.96 grams of the piperazinone directly as a white solid.[α]_(D) ²⁵=+14.8° (CH₃OH, c=0.834 g/dL). ESI MS: (M+H)⁺=295.2. ¹H NMR(300 MHz, CDCl₃) δ 7.36-7.20 (m, 4H), 7.18 (d, J=7 Hz, 1H), 5.84 (bs,1H), 3.73-3.65 (m, 1H), 3.57-4,48 (dd, J=5 Hz, J=22 Hz, 2H), 3.20-3.16(dd, J=4 Hz, J=13 Hz, 1H), 2.92-2.85 (dd, J=5 Hz, J=13 Hz, 1H),2.77-2.62 (overlap dd, 2H), 1.78 (bs, 1H). [Note: A sample of samepiperazinone synthesized using the method of EXAMPLE 1 above gave an[α]_(D) ²⁵=+35.1° (CH₃OH, c=0.462 g/dL)].

Example 54-((1R,2R)-2-Amino-cyclohexylmethyl)-(6S)-6-benzyl-piperazin-2-one

Part 1.{(1R,2S)-2-[(3S)-3-benzyl-5-oxo-piperazin-1-ylmethyl]-cyclohexyl}-carbamicacid benzyl ester.

A solution of cyclohexyl aldehyde from EXAMPLE 2 above (1.7 g, 6.5 mmol)and piperazinone from EXAMPLE 4 above (1.0 g, 5.3 mmol) in CH₂Cl₂ (50ml) was treated with Na(OAc)₃BH (1.5 g, 7.0 mmol). The resulting mixturewas stirred at room temperature for 4 hours (until reaction was judgedto be complete by TLC). The mixture was quenched with 1N NaOH (50 ml)and stirred for 30 minutes. The organic layer separated and washed withwater, and brine. The extract was dried over MgSO₄, filtered andconcentrated on a rotary evaporator to give white solid. This waschromatographed on silica gel (EtOAc) to give 1.7 grams of product as awhite solid. ¹H NMR (300 MHz, CDCl₃) δ 7.36-7.29 (m, 8H), 7.06-7.04 (m,2H), 5.81 (bs, 1H), 5.67 (bs, 1H), 5.09 (bs, 2H), 3.65 (bm, 1H),3,25-3.20 (m, 1H), 3.20 (d, J=16 Hz, 1H), 3.01 (d, J=16 Hz, 1H),2.83-2.51 (m, 5H), 2.40-2.22 (m, 1H), 2.29-2.16 (m, 2H), 1.85-1.81 (m,1H), 1.74-1.70 (m, 2H), 1.40-0.96 (m, 5H). ESI MS: (M+H)⁺=436.2.Part 2.4-((1R,2R)-2-Amino-cyclohexylmethyl)-(6S)-6-(4-fluoro-benzyl)-piperazin-2-one.

A solution of N-CBZ cyclohexyl piperazinone from part 1 above (1.7 g,3.9 mmol) in methanol (200 ml) was treated with 2 g of 10% Pd/C andhydrogenated at 60 psi of hydrogen for 15 hours. The mixture is filteredand the solvent removed on a rotary evaporator to give 1.1 grams of thefree amino cyclohexyl piperazinone as a white solid. ¹H NMR (300 MHz,CDCl₃) δ 7.36-7.27 (m, 3H), 7.20-7.18 (m, 2H), 6.05 (bs, 1H), 3.74 (m,1H), 3.30 (d, J=16 Hz, 1H), 2.96 (d, J=16 Hz, 1H), 2.93-2.78 (m, 4H),2.71-2.58 (m, 4H), 2.50-2.39 (m, 1H), 2.33 (dd, J=7 Hz, J=12 Hz, 1H),2.20 (dd, J=7 Hz, J=12 Hz, 1H), 2.02 (bs, 2H), 1.91-1.69 (m, 4H),1.38-0.85 (m, 5H). ESI MS: (M+H)⁺=302.3; HRMS: (M+H)⁺=302.2235.

Example 6 (5-Acetyl-4-methyl-thiazol-2-yl)-carbamic acid phenyl ester

In a round-bottom flask, NaH 60% dispersion in mineral oil (3.07 g, 77mmol) was washed 2× with hexane and suspended in DMF. Then2-amino-5-acetyl-4-methyl-thiazole (10.0 g, 64 mmol) was added andstirred while cooling in an ice bath. Stirring continued until the NaHwas consumed. Diphenyl carbonate (34 g, 160 mmol) was added whilecooling and after the addition was complete the reaction mixture wasstirred for an additional ˜30 minutes at room temperature. The DMF wasremoved on a rotary evaporator (high vacuum, 40° C.) to yield a brownresidue. This residue was dissolved in 1 L of CHCl₃ and washedsuccessively with 2 L of 0.5N HCl, 2×1 L of water, and finally by 1 L ofbrine. The aqueous portions were back extracted twice with ˜300 mL ofCHCl₃. The combined organic fractions were dried over anhydrous sodiumsulfate, filtered and concentrated on a rotary evaporator to give awhite solid. This was chromatographed on silica (15%-70% EtOAc/hexane)to give 15 g of the desired carbamate as a white solid. ¹H NMR (300 MHz,CDCl₃) δ 11.42 (bs, 1H), 7.47-7.40 (m, 2H), 7.33-7.27 (m, 1H), 7.22-7.18(m, 2H), 2.72 (s, 3H), 2.50 (s, 3H). ESI MS: (M+H)⁺=277.1.

Example 7N-(3-Acetyl-phenyl)-N′-[3-((3S)-3-benzyl-5-oxo-piperazin-1-yl)-propyl]-urea

Part 1. 4-(3-Amino-propyl)-(6S)-6-benzyl-piperazin-2-one.

A solution of (6S)-6-benzyl-piperazin-2-one (0.5 g, 2.6 mmol) in DMF wastreated with N.N-di-Boc-3-bromo-propylamine (1.0 g, 2.9 mmol) and K₂CO₃(0.5 g, 3.6 mmol) and stirred overnight at room temperature. Thereaction mixture was diluted with water and extracted into EtOAc andwashed with water, and brine. The extract was dried over MgSO₄, filteredand concentrated on a rotary evaporator to give crude alkylatedpiperazin-2-one as an oil. The crude oil was dissolved in CH₂Cl₂ (25 ml)and treated with TFA (25 ml) at room temperature for 1 hour. The solventwas removed under vacuum on a rotary evaporator to give a syrup that wasneutralized with 1 N NaOH. The basic solution was extracted into EtOAcand washed with water, and brine. The extract was dried over MgSO₄,filtered and concentrated on a rotary evaporator to give 0.2 g of crudeamine that was used without further purification.Part 2.N-(3-Acetyl-phenyl)-N′-[3-((3S)-3-benzyl-5-oxo-piperazin-1-yl)-propyl]-urea.

A solution of crude amine from part 1 above (0.2 g, 0.8 mmol) in THF wastreated with 3-acetyl-phenylisocyanate (0.16 g, 1.0 mmol) and stirred atroom temperature for 30 minutes. The solvents were removed under vacuumon a rotary evaporator and the residue chromatographed on silica gel(first EtOAc; then 10% MeOH/EtOAc) to give-100 mg of desired urea as awhite solid. ¹H NMR (300 MHz, CDCl₃/CD₃OD) δ 7.95 (bs, 1H), 7.87 (m,1H), 7.71 (dd, J=1 Hz, J=8 Hz, 1H), 7.55 (d, J=8 Hz, 1H), 7.37-7.23 (m,4H), 7.14 (d, J=7 Hz, 2H), 6.20 (bs, 1H), 5.87 (bs, 1H), 3.75 (m, 1H),3.46-3.30 (m, 3H), 3.04 (d, J=16 Hz 1H), 2.94-2.55 (m, 5H), 2.57 (s,3H), 2.38 (m, 1H), 1.86 (m, 2H), 1.74 (q, J=7 Hz, 2H). ESI MS:(M+H)⁺=409.2.

Example 8N-(5-Acetyl-4-methyl-thiazol-2-yl)-N′-{(1R,2S)-2-[(3S)-3-(4-fluoro-benzyl)-5-oxo-piperazin-1-ylmethyl]-cyclohexyl}-urea

A solution of amine from EXAMPLE 3 (75 mg, 0.23 mmol) and carbamate fromEXAMPLE 6 (65 mg, 0.23 mmol) in ACCN (4 ml) was warm to 45° C. for 30minutes. A solid form and the mixture cooled to room temperature and thesolid filtered off to give 50 mg of the desired urea. ¹H NMR (300 MHz,CDCl₃) δ 12.21 (bs, 1H), 8.56 (bs, 1H), 6.99-6.90 (m, 4H), 5.49 (bd, J=8Hz, 1H), 3.52 (m, 1H), 3.40 (m, 1H), 3.24 (d, J=17 Hz, 1H), 2.96 (d,J=17 Hz, 1H), 2.88 (dd, J=5 Hz, J=14 Hz, 1H), 2.73 (dd, J=9 Hz, J=14 Hz,1H), 2.54 (m, 2H), 2.47 (s, 6H), 2.20-2.06 (m, 3H), 1.90-1.76 (m, 4H),1.43-1.00 (m, 4H). ESI MS: (M+H)⁺=502.2; HRMS: (M+H)⁺=502.2287.

Example 9N-(5-Acetyl-4-methyl-thiazol-2-yl)-N′-{(1R,2R)-2-[(3S)-3-(4-fluoro-benzyl)-2,5-dioxo-piperazin-1-ylmethyl]-cyclohexyl}-urea

Part 1.[(1S,2R)-(2-Benzyloxycarbonylamino-cyclohexylmethyl)-amino]-acetic acidmethyl ester.

A solution of aldehyde from Example 2 above (5.0 g, 19.1 mmol) andglycine methyl ester HCl (4.80 g, 38.3 mmol) in DMSO (80 ml) was treatedwith Na(OAc)₃BH (8.92 g, 42.08 mmol) and stirred overnight at roomtemperature. Reaction was quenched by adding water drop-wise and madebasic to pH 12 with 1 N NaOH. The aqueous mixture was extracted intoEtOAc and washed with water, and brine. The extract was dried overMgSO₄, filtered and concentrated on a rotary evaporator to give aresidue that was chromatographed on silica (30% EtOAc/hexane) to give5.37 g of amine product.Part 2.{((1R,2S)-2-Benzyloxycarbonylamino-cyclohexylmethyl)-[(2S)-2-tert-butoxycarbonylamino-3-(4-fluoro-phenyl)-propionyl]-amino}-aceticacid methyl ester.

A solution of the amine obtained in part 1 above (1.0 g, 2.99 mmol),N-Boc-4-F-phenylalanine (1.02 g, 3.59 mmol), and HOBT (0.81 g, 5.98mmol) in CH₂Cl₂ was treated with DCC (0.74 g, 3.59 mmol) and stirred atroom temperature for 48 hours. The reaction mixture was washed withwater, brine, and dried over MgSO₄. The drying agent was filtered andthe solvent removed under vacuum on a rotary evaporator to give aresidue that was chromatographed on silica (50% EtOAc/hexane to 100%EtOAc) to give 1.04 g of the amide.Part 3.{(1R,2R)-2-[(3S)-3-(4-Fluoro-benzyl)-2,5-dioxo-piperazin-1-ylmethyl]-cyclohexyl}-carbamicacid benzyl ester.

A solution of the amide from part 2 above (0.98 g, 1.63 mmol) in 30 mlof TFA/CH₂Cl₂ (2:1) was stirred at room temperature for 2 hours. Thesolvent was removed on a rotary evaporator to give a thick syrup. Thissyrup was dissolved in methanol (200 ml) and made basic to pH 12 with 1NNaOH. Most of the methanol was removed on a rotary evaporator and thendiluted with water and extracted into EtOAc. The organic extracts werewashed with water, and brine. The extract was dried over Na₂SO₄,filtered and concentrated on a rotary evaporator to give a residue thatwas chromatographed on silica gel (100% EtOAc) to give 0.37 grams of thepiperazine-2,5-dione as a white solid.Part 4.1-((1R,2R)-2-Amino-cyclohexylmethyl)-(3S)-3-(4-fluoro-benzyl)-piperazine-2,5-dione.

A solution of the piperazine-2,5-dione from part 3 above (0.37 g, 0.23mmol) in MeOH (20 ml) was treated with 20 mg of 10% Pd/C andhydrogenated at 45 psi of hydrogen for 15 hours. The mixture is filteredand the solvent removed on a rotary evaporator to give 0.28 grams of thefree amino which was used without further purification.Part 5.N-(5-Acetyl-4-methyl-thiazol-2-yl)-N′-{(1R,2R)-2-[(3S)-3-(4-fluoro-benzyl)-2,5-dioxo-piperazin-1-ylmethyl]-cyclohexyl}-urea.

A solution of amine from part 4 (80 mg, 0.23 mmol) in DMF (10 ml) istreated with 5-Acetyl-4-methyl-thiazol-2-yl carbamate from EXAMPLE 6 (63mg, 0.26 mmol) and stirred overnight at room temperature. The mixturewas diluted with water and extracted into EtOAc. The organic extractswere washed with water, and brine. The extract was dried over Na₂SO₄,filtered and concentrated on a rotary evaporator to give a residue thatwas chromatographed on silica gel (1:9:90 NH₃/MeOH/CHCl₃) to givedesired urea. ¹H NMR (300 MHz, CDCl₃) δ 7.16-7.12 (m, 2H), 6.99 (t, J=11Hz, 2H), 6.15 (bs, 1H), 4.27 (t, J=5 Hz, 1H), 3.61-3.42 (m, 3H), 3.22(dd, J=5 Hz, J=6 Hz, 1H), 3.09-2.97 (m, 3H), 2.54 (s, 3H), 2.47 (s, 3H),2.12 (d, J=10 Hz, 1H), 1.72-1.11 (m, 9H). ESI MS: (M+H)⁺=516.2.

Example 10 N-(5-Acetyl-4-methyl-thiazol-2-yl) —N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-(2S)-2-hydroxymethyl-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea

Part 1.(2S)-2-[(2S)-2-tert-Butoxycarbonylamino-3-(4-fluoro-phenyl)-propylamino]-3-hydroxy-propionicacid methyl ester

A solution of N-Boc-4-fluorophenylalinal from Example 1 above (2.0 g,7.48 mmol) and serine methyl ester HCl (1.17 g, 7.48 mmol) in DMSO (50ml) was treated with Na(OAc)₃BH (2.37 g, 11.2 mmol) and stirredovernight at room temperature. Reaction was quenched by adding waterdrop-wise and made basic to pH 12 with 1 N NaOH. The aqueous mixture wasextracted into EtOAc and washed with water, and brine. The extract wasdried over Na₂SO₄, filtered and concentrated on a rotary evaporator togive 2.5 g of crude amine product as a white solid.Part 2.(2S)-2-{((1S,2R)-2-Benzyloxycarbonylamino-cyclohexylmethyl)-[(2S)-2-tert-butoxycarbonylamino-3-(4-fluoro-phenyl)-propyl]-amino}-3-hydroxy-propionicacid methyl ester

A solution of cyclohexyl aldehyde from EXAMPLE 2 above (1.35 g, 5.18mmol) and amine from part 1 above (1.92 g, 5.18 mmol) in CH₂Cl₂ (50 ml)was treated with Na(OAc)₃BH (1.65 g, 7.77 mmol). The resulting mixturewas stirred at room temperature overnight. The mixture was quenched with1 N NaOH (50 ml) and stirred for 30 minutes. The organic layer separatedand washed with water, and brine. The extract was dried over Na₂SO₄,filtered and concentrated on a rotary evaporator to give a residue. Thiswas chromatographed on silica gel (30% EtOAc/Hexane) to give 1.69 gramsof amino alcohol product.Part 3.{(1R,2S)-2-[(5S)-5-(4-Fluoro-benzyl)-(2S)-2-hydroxymethyl-3-oxo-piperazin-1-ylmethyl]-cyclohexyl}-carbamicacid benzyl ester

A solution of the amino alcohol from part 2 above (1.69 g, 2.74 mmol) in30 ml of TFA/CH₂Cl₂ (2:1) was stirred at room temperature for 1 hours.The solvent was removed on a rotary evaporator to give a thick syrup.This syrup was dissolved in methanol (200 ml) and made basic to pH 12with 1N NaOH. Most of the methanol was removed on a rotary evaporatorand then diluted with water and extracted into EtOAc. The organicextracts were washed with water, and brine. The extract was dried overNa₂SO₄, filtered and concentrated on a rotary evaporator to give 1.3 gof the piperazin-2-one as a white solid.Part 4.4-((1S,2R)-2-Amino-cyclohexylmethyl)-(6S)-6-(4-fluoro-benzyl)-(3S)-3-hydroxymethyl-piperazin-2-one.

A solution of the piperazin-2-one from part 3 above (1.33 g, 2.75 mmol)in MeOH (50 ml) was treated with 1 g of 10% Pd/C and hydrogenated at 45psi of hydrogen for 15 hours. The mixture is filtered and the solventremoved on a rotary evaporator to give 0.9 grams of the free amino whichwas used without further purification.Part 5.N-(5-Acetyl-4-methyl-thiazol-2-yl)-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-(2S)-2-hydroxymethyl-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.

A solution of amine from part 4 above (130 mg, 0.36 mmol) and carbamatefrom EXAMPLE 6 (100 mg, 0.36 mmol) in AcCN (5 ml) was stirred overnightat room temperature. The solvents were removed under vacuum on a rotaryevaporator and the residue chromatographed on silica gel (5% MeOH/EtOAc)to give the desired urea as a white solid. ¹H NMR (300 MHz, DMSO) δ10.68 (br s, 1H), 7.84 (s, 1H), 7.23-7.18 (m, 2H), 7.08 (t, J=9 Hz, 2H),6.70 (br s, 1H), 4.57 (br s, 1H), 3.61 (br s, 2H), 3.31 (s, 2H),2.88-2.73 (m, 4H), 2.51 (s, 3H), 2.43 (s, 3H), 2.37 (m, 1H), 2.36 (m,1H), 2.15 (m, 1H), 1.89-1.15 (m, 9H). ESI MS: (M+H)⁺=532.3.

Example 27 N-[(1R,2S)-2-[(2S)-2-Benzyl-6-oxo-morpholin-4-ylmethyl]-cyclohexyl]-N′-phenyl-urea

Part 1. 3-Phenyl-(2S)-2-(tetrahydro-pyran-2-yloxy)-propionic acid methylester

A solution of L-phenyl lactic acid methyl ester (20.0 g, 111 mmol) inCH₂Cl₂ (300 mL) was treated with dihydropyran (9.32 g, 111 mmol) andp-toluenesulphonic acid (56 mg) and stirred at room temperature for 20minutes. The reaction is quenched with 1 N NaOH and then washed withwater, brine and dried over Na₂SO₄. The solution is filtered and thesolvent removed under vacuum to give 28 grams of the THP protectedalcohol as an oil. This was used without further purification.Part 2. 3-Phenyl-(2S)-2-(tetrahydro-pyran-2-yloxy)-propan-1-ol

A solution of crude THP protected alcohol ester from Part 1 (28 g, 106mmol) in ether (300 ml) was cooled in an ice bath and treated with solidLAH (5.0 g, 130 mmol) a small portion at a time [Caution: foaming]. Thesolution is stirred for 2 hours while cooling in the ice bath. Thereaction is quenched by drop-wise addition of 5 ml of water followed by20 ml of 1 N NaOH [Caution: foaming]. The resulting suspension isstirred for 30 minutes and then filtered and the solids washed withether. The ether filtrates were dried over Na₂SO₄, the drying agentfiltered off, and the solvent removed under vacuum to give 22 g of diolas an oil.Part 3. 3-Phenyl-(2S)-2-(tetrahydro-pyran-2-yloxy)-propionaldehyde

A solution of DMSO (6.3 g, 75 mmol) in methylene chloride was cooled to−78° C. in a dry ice/acetone bath and treated drop-wise with oxalylchloride (7.0 g, 55 mmol). After the addition was complete, theresulting mixture was stirred for 15 minutes at −78° C. A solution ofthe alcohol from part 2 (6.6 g, 28 mmol) in CH₂Cl₂ (100 ml) was thenadded slowly to the reaction mixture via an addition funnel and stirredfor another 15 minutes. Then 20 ml of Et₃N was added drop-wise and theresulting mixture was stirred for 10 minutes before removing the dryice/acetone bath and allowing the mixture to warm to room temperature.The solution is diluted with water and the organic layer washed withwater, 1 N HCl, and brine. The organic layer is dried over Na₂SO₄,filtered, and concentrated to give 6.6 g (9.5 mmol) of the crudealdehyde as an oil.Part 4.[3-(4-Fluoro-phenyl)-(2S)-2-(tetrahydro-pyran-2-yloxy)-propyl]-((1R)-1-phenyl-ethyl)-amine

A solution of crude aldehyde from part 3 above (6.6 g, 28 mmol) inCH₂Cl₂ (100 ml) was treated with R-α-methylbenzyl amine (3.4 g, 28 mmol)and Na(OAc)₃BH (8.9 g, 42 mmol). The resulting mixture was stirred atroom temperature overnight. The mixture was quenched with 1 N NaOH (50ml) and stirred for 30 minutes. The organic layer separated and washedwith water, and brine. The extract was dried over MgSO₄, filtered andconcentrated on a rotary evaporator to give a thick oil. This waschromatographed on silica gel (50% EtOAc/Hexane) to give 3.38 g grams ofone amine diastereomer and 2.65 g of a second amine diastereomer. Anadditional 0.5 g of a mixture of diastereomers was also obtained.Part 5.{((1R)-1-Phenyl-ethyl)-[3-phenyl-(2S)-2-(tetrahydro-pyran-2-yloxy)-propyl]-amino}-aceticacid methyl ester

A solution of the amine from part 4 above (3.38 g, 10 mmol) in DMF (20ml) was treated with methyl bromoacetate (2.29 g, 15 mmol) and K₂CO₃(2.0 g, 15 mmol). The resulting mixture stirred overnight at roomtemperature. The reaction mixture was diluted with 300 ml of water andextracted into EtOAc. The organic extracts were washed with water, andbrine. The extract was dried over MgSO₄, filtered and concentrated on arotary evaporator to give 4.1 g of the amine ester as a thick oil andwas used without further purification.Part 6. (6S)-6-Benzyl-4-((1S)-1-phenyl-ethyl)-morpholin-2-one

The crude amine ester (4.1 g, 10 mmol) from Part 5 was dissolved inmethanol and treated with 1 ml of H₂SO₄ and heated to reflux for 2hours. Most of the methanol was then removed under vacuum on a rotaryevaporator and the resulting residue neutralized with 1 N NaOH andextracted into EtOAc. The organic extract was washed with water andbrine. The organic solvent was removed on a rotary evaporator and theresulting residue chromatographed on silica gel (15% EtOAc/hexane) togive 1.8 grams of morpholinone as an oil.Part 7. (6S)-6-Benzyl-morpholin-2-one

A solution of N-benzyl morpholin-2-one from part 6 (1.8 g, 6.1 mmol) inmethanol (100 ml) was treated with 0.5 g of 10% Pd(OH)₂/C andhydrogenated at 60 psi of hydrogen for 15 hours. The mixture is filteredand the solvent removed under vacuum on a rotary evaporator to give 1.16grams of the morpholin-2-one as an oil.Part 8.[(1R,2S)-2-(2-Benzyl-6-oxo-morpholin-4-ylmethyl)-cyclohexyl]-carbamicacid benzyl ester

A solution of cyclohexyl aldehyde from EXAMPLE 2 above (1.6 g, 6.1 mmol)and morpholin-2-one from Part 7 above (1.16 g, 6.0 mmol) in CH₂Cl₂ (50ml) was treated with Na(OAc)₃BH (1.93 g, 9.1 mmol). The resultingmixture was stirred at room temperature for 4 hours (until reaction wasjudged to be complete by TLC). The mixture was quenched with 1N NaOH (50ml) and stirred for 30 minutes. The organic layer separated and washedwith water, and brine. The extract was dried over MgSO₄, filtered andconcentrated on a rotary evaporator to give a thick oil. This waschromatographed on silica gel (25% EtOAc/Hexane) to give 1.2 grams ofproduct as a white solid.Part 9.4-((1R,2R)-2-Amino-cyclohexylmethyl)-(6S)-6-benzyl-morpholin-2-one

A solution of N-CBZ cyclohexyl morpholin-2-one from part 8 above (1.2 g,2.7 mmol) in methanol (100 ml) was treated with 0.5 g of 10% Pd/C andhydrogenated at 60 psi of hydrogen for 15 hours. The mixture is filteredand the solvent removed on a rotary evaporator to give 0.83 grams of thefree amino cyclohexyl morpholin-2-one as a white solid.Part 10.N-[(1R,2S)-2-[(2S)-2-Benzyl-6-oxo-morpholin-4-ylmethyl]-cyclohexyl]-N′-phenyl-urea

A solution of crude amine from part 9 above (75 mg, 0.25 mmol) in THFwas treated with phenylisocyanate (30 mg, 0.25 mmol) and stirred at roomtemperature for 30 minutes. The solvents were removed under vacuum on arotary evaporator and the residue chromatographed on silica gel (25%-50%EtOAc/Hexane) to give 30 mg of desired urea as a white solid. ¹H NMR(300 MHz, CDCl₃) δ 7.33-7.19 (m, 7H), 7.05-7.00 (m, 3H), 6.92 (bs, 1H),5.69 (d, J=8 Hz, 1H), 4.40 (m, 1H), 3.50 (d, J=18 Hz, 1H), 3.43 (, 1H),2.93 (d, J=18 Hz, 1H), 2.90(abx m, 2H), 2.62 (m, 2H), 2.31-2.03 (m, 3H),1.66 (m, 2H), 1.34-0.81 (m, 5H). ESI MS: (M+H)⁺=422.2.

The following compounds in Table 1 were prepared by the above methods orby methods familiar to one skilled in the art:

TABLE 1

MS Ex (M + # Core R⁵ R³ R¹⁷ H) +  7 6 (S) CH2Ph 3-Ac-Ph H 409.2  8 1 (S)CH2Ph(4-F) 4-Me-5-Ac-Thiazole H 502.2  9 2 (S) CH2Ph(4-F)4-Me-5-Ac-Thiazole H 516.2 10 3 (S) CH2Ph(4-F) 4-Me-5-Ac-Thiazole H532.3 11 4 (S) CH2Ph(4-F) 4-Me-5-Ac-Thiazole H 532.3 12 1 (S) CH2Ph(4-F)4-Me-5-Ac-Thiazole Me 611.3 13 1 (S) CH2Ph(3-F) 4-Me-5-Ac-Thiazole H502.2 14 1 (S) CH2Ph(2-F) 4-Me-5-Ac-Thiazole H 502.2 15 2 (S) CH2Ph4-Me-5-Ac-Thiazole H 498.2 16 1 (S) CH2Ph 4-Me-5-Ac-Thiazole H 484.3 171 (R) CH2Ph(4-F) 4-Me-5-Ac-Thiazole H 502.2 18 1 (S) CH2Ph(4-Cl)4-Me-5-Ac-Thiazole H 518.2 19 1 (R) CH2PhC4-Cl) 4-Me-5-Ac-Thiazole H518.2 20 1 (S) CH2CH2Ph 4-Me-5-Ac-Thiazole H 498.3 21 1 H4-Me-5-Ac-Thiazole 4-F-Bn 502.5 23 1 (S) CH2Ph Ph H 421.1 24 1 (R) CH2PhPh H 421.1 25 5 (S) CH2Ph Ph H 445.3 26 1 H Ph 4-F-Bn 439.5 27 7 (S)CH2Ph Ph — 422.2 28 1 (S) CH2Ph 3-CN-Ph H 446.3 29 5 (S) CH2Ph 3-CN-Ph H470.1 30 1 (S) CH2Ph(4-F) 3-Ac-4-F-Ph H 499.3 31 5 (S) CH2Ph 3-Ac-Ph H487.3 32 1 (S) CH2Ph 3-Ac-Ph H 463.3 33 1 (S) CH2Ph(4-F) 3-Ac-Ph H 481.234 1 (S) CH2Ph(3-F) 3-Ac-Ph H 481.3 35 1 (S) CH2Ph(2-F) 3-Ac-Ph H 481.236 3 (S) CH2Ph(4-F) 3-Ac-Ph H 511.3 37 4 (S) CH2Ph(4-F) 3-Ac-Ph H 511.338 1 (S) CH2Ph(4-F) 3-Ac-Ph Me 495.3 39 1 (S) CH2Ph(4-F) 3-Ac-Ph Bn571.3 40 2 (S) CH2Ph(4-F) 3-Ac-Ph H 477.1 41 1 (R) CH2Ph(4-F) 3-Ac-Ph H481.3 42 1 (S) CH2Ph(4-Cl) 3-Ac-Ph H 497.4 43 1 (S) CH2Ph(3-CN) 3-Ac-PhH 488.4 44 1 (R) CH2Ph(3- 3-Ac-Ph H 488.4 CN) 45 1 (S) CH2CH2Ph 3-Ac-PhH 477.3 46 1 H 3-Ac-Ph 4-F-Bn 481.6 47 7 (S) CH2Ph 3-Ac-Ph — 464.6 49 4(S) CH2Ph(4-F) 3-(1-Hydroxy-ethyl)-Ph H 513.5 51 2 (S) CH2Ph(4-F)5-indazole H 493.2 52 2 (S) CH2Ph 5-indazole H 475.1 53 1 (S) CH2Ph5-indazole H 461.3 54 1 (S) CH2Ph(4-F) 5-indazole H 479.2 55 1 (S)CH2Ph(4-F) 3,5-di-Ac-Ph H 523.3 56 1 (S) CH2Ph(3-F) 3,5-di-Ac-Ph H 523.457 1 (S) CH2Ph(2-F) 3,5-di-Ac-Ph H 523.2 58 1 (S) CH2Ph(4-F)3,5-di-Ac-Ph Me 537.5 59 1 (R) CH2Ph(4-F) 3,5-di-Ac-Ph H 523.3 60 1 (S)CH2CH2Ph 3,5-di-Ac-Ph H 519.3 63 7 (S) CH2Ph 3,5-di-Ac-Ph — 506.3 64 1(S) CH2Ph(4-F) 3,5-di-Ac-Ph Bn 613.3 65 1 (S) CH2Ph(4-F)3-(Me-Tetrazole)-Ph H 521.3 66 1 (S) CH2Ph(2-F) 3-(Me-Tetrazole)-Ph H521.3 67 3 (S) CH2Ph(4-F) 3-(Me-Tetrazole)-Ph H 551.3 68 4 (S)CH2Ph(4-F) 3-(Me-Tetrazole)-Ph H 551.3 69 1 (S) CH2Ph(4-F)3-(Me-Tetrazole)-Ph Me 535.3 70 1 (S) CH2Ph(4-F) 3-(Me-Tetrazole)-Ph Bn611.3 71 1 (R) CH2Ph(4-F) 3-(Me-Tetrazole)-Ph H 521.3 72 1 (S)CH2Ph(4-Cl) 3-(Me-Tetrazole)-Ph H 537.5 73 1 (S) CH2Ph(3-CN)3-(Me-Tetrazole)-Ph H 528.4 74 1 (R) CH2Ph(3- 3-(Me-Tetrazole)-Ph H528.4 CN) 75 1 (S) CH2CH2Ph 3-(Me-Tetrazole)-Ph H 517.3 78 1 H3-(Me-Tetrazole)-Ph 4-F-Bn 521.1 79 7 (S) CH2Ph 3-(Me-Tetrazole)-Ph —504.2 81 1 (S) CH2Ph(4-F) 5-indoline H 480.3 82 1 (S) CH2Ph(3-F)5-indoline H 480.4 83 1 (S) CH2Ph(4-F) 4-Me-2-Thiazole H 460.2 84 1 (S)CH2Ph(4-F) 2-Thiadiazole H 447.2 85 1 (S) CH2Ph(4-F) 1-Me-3-Pyrazole H443.3 86 1 (S) CH2Ph(4-F) 2-Thiazole H 446.2

The following contains representative examples of the present invention,and may be prepared by procedures described above, or methods familiarto one skilled in the art. Each entry in each of the tables (R³ and R⁵)is intended to be paired with each core 1-7 shown at the beginning ofthe tables.

R³ 1. 3-CN-Ph 2. 3-COCH3-Ph 3. 3-CO2Me-Ph 4. 3-CO2Et-Ph 5. 3-CO2H-Ph 6.3-CONH2-Ph 7. 3-CONHMe-Ph 8. 3-F-Ph 9. 3-Cl-Ph 10. 3-Br-Ph 11. 3-NO2-Ph12. 3-NH2-Ph 13. 3-NHMe-Ph 14. 3-NMe2-Ph 15. 3-NHCOCH3-Ph 16.3-SO2NH2-Ph 17. 3-SO2NHMe-Ph 18. 3-CF3-Ph 19. 3-OCH3-Ph 20. 3-OPh-Ph 21.3-OCF3-Ph 22. 3-SCH3-Ph 23. 3-SOCH3-Ph 24. 3-SO2CH3-Ph 25. 3-OH-Ph 26.3-CH2OH-Ph 27. 3-CHOHCH3-Ph 28. 3-COH(CH3)2-Ph 29. 3-CHOHPh-Ph 30.3-CH3-Ph 31. 3-C2H5-Ph 32. 3-iPr-Ph 33. 3-tBu-Ph 34. 3-Ph—Ph 35.3-CH2Ph-Ph 36. 3-CH2CO2Me-Ph 37. 3-(1-piperidinyl)-Ph 38.3-(1-pyrrolidinyl)-Ph 39. 3-(2-imidazolyl)-Ph 40. 3-(1-imidazolyl)-Ph41. 3-(2-thiazolyl)-Ph 42. 3-(3-pyrazolyl)-Ph 43. 3-(1-pyrazolyl)-Ph 44.3-(1-tetrazolyl)-Ph 45. 3-(5-tetrazolyl)-Ph 46. 3-(2-pyridyl)-Ph 47.3-(2-thienyl)-Ph 48. 3-(2-furanyl)-Ph 49. 4-CN-Ph 50. 4-COCH3-Ph 51.4-CO2Me-Ph 52. 4-CO2Et-Ph 53. 4-CO2H-Ph 54. 4-CONH2-Ph 55. 4-CONHMe-Ph56. 4-CONHPh-Ph 57. 4-NHCONH2-Ph 58. 4-F-Ph 59. 4-Cl-Ph 60. 4-Br-Ph 61.4-NO2-Ph 62. 4-NH2-Ph 63. 4-NHMe-Ph 64. 4-NMe2-Ph 65. 4-NHCOCH3-Ph 66.4-SO2NH2-Ph 67. 4-SO2NHMe-Ph 68. 4-CF3-Ph 69. 4-OCH3-Ph 70. 4-OPh-Ph 71.4-OCF3-Ph 72. 4-SCH3-Ph 73. 4-SOCH3-Ph 74. 4-SO2CH3-Ph 75. 4-OH-Ph 76.4-CH2OH-Ph 77. 4-CHOHCH3-Ph 78. 4-COH(CH3)2-Ph 79. 4-CH3-Ph 80.4-C2H5-Ph 81. 4-iPr-Ph 82. 4-tBu-Ph 83. 4-Ph—Ph 84. 4-CH2Ph-Ph 85.4-CH2CO2Me-Ph 86. 4-(1-piperidinyl)-Ph 87. 4-(1-pyrrolidinyl)-Ph 88.4-(2-imidazolyl)-Ph 89. 4-(1-imidazolyl)-Ph 90. 4-(2-thiazolyl)-Ph 91.4-(3-pyrazolyl)-Ph 92. 4-(1-pyrazolyl)-Ph 93. 4-(1-tetrazolyl)-Ph 94.4-(5-tetrazolyl)-Ph 95. 4-(2-pyridyl)-Ph 96. 4-(2-thienyl)-Ph 97.4-(2-furanyl)-Ph 98. 2-CN-Ph 99. 2-COCH3-Ph 100. 2-CO2Me-Ph 101.2-CO2Et-Ph 102. 2-CO2H-Ph 103. 2-CONH2-Ph 104. 2-CONHMe-Ph 105. 2-F-Ph106. 2-Cl-Ph 107. 2-Br-Ph 108. 2-NO2-Ph 109. 2-NH2-Ph 110. 2-NHMe-Ph111. 2-NMe2-Ph 112. 2-NHCOCH3-Ph 113. 2-SO2NH2-Ph 114. 2-SO2NHMe-Ph 115.2-CF3-Ph 116. 2-OCH3-Ph 117. 2-OPh-Ph 118. 2-OCF3-Ph 119. 2-SCH3-Ph 120.2-SOCH3-Ph 121. 2-SO2CH3-Ph 122. 2-OH-Ph 123. 2-CH2OH-Ph 124.2-CHOHCH3-Ph 125. 2-COH(CH3)2-Ph 126. 2-CHOHPh-Ph 127. 2-CH3-Ph 128.2-C2H5-Ph 129. 2-iPr-Ph 130. 2-tBu-Ph 131. 2-Ph—Ph 132. 2-CH2Ph-Ph 133.2-CH2CO2Me-Ph 134. 2-(1-piperidinyl)-Ph 135. 2-(1-pyrrolidinyl)-Ph 136.2-(2-imidazolyl)-Ph 137. 2-(1-imidazolyl)-Ph 138. 2-(2-thiazolyl)-Ph139. 2-(3-pyrazolyl)-Ph 140. 2-(1-pyrazolyl)-Ph 141. 2-(1-tetrazolyl)-Ph142. 2-(5-tetrazolyl)-Ph 143. 2-(2-pyridyl)-Ph 144. 2-(2-thienyl)-Ph145. 2-(2-furanyl)-Ph 146. 2,4-diF-Ph 147. 2,5-diF-Ph 148. 2,6-diF-Ph149. 3,4-diF-Ph 150. 3,5-diF-Ph 151. 2,4-diCl-Ph 152. 2,5-diCl-Ph 153.2,6-diCl-Ph 154. 3,4-diCl-Ph 155. 3,5-diCl-Ph 156. 3,4-diCF3-Ph 157.3,5-diCF3-Ph 158. 5-Cl-2-MeO-Ph 159. 5-Cl-2-Me-Ph 160. 2-F-5-Me-Ph 161.2-F-5-NO2-Ph 162. 3,4-OCH2O-Ph 163. 3,4-OCH2CH2O-Ph 164. 2-MeO-4-Me-Ph165. 2-MeO-5-Me-Ph 166. 1-naphthyl 167. 2-naphthyl 168. 2-thienyl 169.3-thienyl 170. 2-furanyl 171. 3-furanyl 172. 2-pyridyl 173. 3-pyridyl174. 4-pyridyl 175. 2-indolyl 176. 3-indolyl 177. 5-indolyl 178.6-indolyl 179. 3-indazolyl 180. 5-indazolyl 181. 6-indazolyl 182.2-imidazolyl 183. 3-pyrazolyl 184. 2-thiazolyl 185. 5-tetrazolyl 186.2-benzimidazolyl 187. 5-benzimidazolyl 188. 2-benzothiazolyl 189.5-benzothiazolyl 190. 2-benzoxazolyl 191. 5-benzoxazolyl 192.1-adamantyl 193. 2-adamantyl 194. 3-(1-methyltetrazol-5-yl)-Ph 195.3-(5-methyltetrazol-1-yl)-Ph 196. 3-(1-ethyltetrazol-5-yl)-Ph 197.3-(1-cyclopropylyltetrazol-5-yl)-Ph 198.3-(1-(2-methoxyethyl)tetrazol-5-yl)-Ph 199.3-(1-(2-cyanoethyl)tetrazol-5-yl)-Ph 200.3-(1-methyltetrazol-5-yl)-5-[(CH3)2N-CO]-Ph 201.3-(1-methyltetrazol-5-yl)-5-[(CH3)NH—CO]-Ph 202.3-(1-methyltetrazol-5-yl)-5-[H2N—CO]-Ph 203.3-(1-methyltetrazol-5-yl)-5-[COCH3]-Ph 204.3-(1-methyltetrazol-5-yl)-5-[morpholin-1-yl-CO]-Ph 205.3-(1-methyltetrazol-5-yl)-5-F-Ph 206. 3-(1-methyltetrazol-5-yl)-5-Cl-Ph207. 3-(1-methyltetrazol-5-yl)-5-Br-Ph 208.3-(1-methyltetrazol-5-yl)-4-F-Ph 209. 3-(1-methyltetrazol-5-yl)-4-Cl-Ph210. 3-(1-methyltetrazol-5-yl)-4-Br-Ph 211.3-(1-methyltetrazol-5-yl)-5-CF3-Ph 212.3-(1-methyltetrazol-5-yl)-4-CF3-Ph 213.3-(1-methyltetrazol-5-yl)-2-CH3O-Ph 214.3-(1-methyltetrazol-5-yl)-4-CH3O-Ph 215.3-(1-methyltetrazol-5-yl)-5-CH3O-Ph 216.3-(1-methyltetrazol-5-yl)-6-CH3O-Ph 217.3-(1-methyltetrazol-5-yl)-5-CH3-Ph 218.3-(1-methyltetrazol-5-yl)-5-CH3CH2-Ph 219.4-(1-methyltetrazol-5-yl)-5-[morpholin-1-yl-CO]-Ph 220.4-(1-methyltetrazol-5-yl)-5-F-Ph 221. 4-(1-methyltetrazol-5-yl)-5-Cl-Ph222. 4-(1-methyltetrazol-5-yl)-5-Br-Ph 223.4-(1-methyltetrazol-5-yl)-3-CF3-Ph 224.4-(1-methyltetrazol-5-yl)-2-CH3O-Ph 225.4-(1-methyltetrazol-5-yl)-5-CH3O-Ph 226. 3,5-bis(morpholin-1-yl)-Ph 227.3,5-bis(1,2,4-triazol-1-yl)-Ph 228. 3,5-bis(pyrazol-1-yl)-Ph 229.3,5-bis(oxazol-2-yl)-Ph 230. 3,5-bis(isoxazol-3-yl)-Ph 231.3,5-bis(isoxazol-5-yl)-Ph 232. 3,5-bis(1,2,3-triazol-1-yl)-Ph 233.3,5-bis(COCH3)-Ph 234. 3,5-bis(CH2OH)-Ph 235. 3-(thiazol-4-yl)-Ph 236.3-(thiazol-5-yl)-Ph 237. 3-(pyrazol-4-yl)-Ph 238.3-(1-methyl-3-pyrazolyl)-Ph 239. 3-(3-isoxazolyl)-Ph 240.3-(4-isoxazolyl)-Ph 241. 3-(5-isoxazolyl)-Ph 242. 1-methyl-5-pyrazolyl243. 1-ethyl-5-pyrazolyl 244. [1,3,4]-oxadiazol-2-yl 245.CO—NH-(2-ethylpyrazol-3-yl) 246. CO—NH-(thiazol-2-yl) 247.CO—NH-(isoxazol-3-yl) 248. 5-acetyl-4-methylthiazol-2-yl 249.5-acetyl-4-methyloxazol-2-yl 250. 5-acetyl-4-methylimidazol-2-yl 251.3-acetyl-5-[(CH3)2N—CO]-Ph 252. 3-acetyl-5-[(CH3)NH—CO]-Ph 253.3-acetyl-5-[H2N—CO]-Ph 254. 3-acetyl-5-[morpholin-1-yl-CO]-Ph 255.3-acetyl-5-F-Ph 256. 3-acetyl-5-Cl-Ph 257. 3-acetyl-5-Br-Ph 258.3-acetyl-4-F-Ph 259. 3-acetyl-4-Cl-Ph 260. 3-acetyl-4-Br-Ph 261.3-acetyl-5-CF3-Ph 262. 3-acetyl-4-CF3-Ph 263. 3-acetyl-2-CH3O-Ph 264.3-acetyl-4-CH3O-Ph 265. 3-acetyl-5-CH3O-Ph 266. 3-acetyl-6-CH3O-Ph 267.3-acetyl-5-CH3-Ph 268. 3-acetyl-5-CH3CH2-Ph 269.4-acetyl-5-[morpholin-1-yl-CO]-Ph 270. 4-acetyl-5-F-Ph 271.4-acetyl-5-Cl-Ph 272. 4-acetyl-5-Br-Ph 273. 4-acetyl-3-CF3-Ph 274.4-acetyl-2-CH3O-Ph 275. 4-acetyl-5-CH3O-Ph 276.3-acetyl-5-(1-methyltetrazol-5-yl)-Ph 277.3-acetyl-5-(1-ethyltetrazol-5-yl)-Ph 278.3-acetyl-5-(1-cyclopropyltetrazol-5-yl)-Ph 279.3-acetyl-5-(oxazol-2-yl)-Ph 280. 3-acetyl-5-(isoxazol-3-yl)-Ph 281.3-acetyl-5-(isoxazol-5-yl)-Ph 282. 3-acetyl-5-(pyrazol-1-yl)-Ph 283.3-acetyl-5-(1,2,4-triazol-1-yl)-Ph 284. 3-acetyl-5-(CH2OH)-Ph 285.3-acetyl-5-(furan-2-yl)-Ph 286. 3-acetyl-5-(furan-3-yl)-Ph 287.3-acetyl-5-(thien-2-yl)-Ph 288. 3-acetyl-5-(thien-3-yl)-Ph 289.3-acetyl-5-CN-Ph 290. 3-acetyl-5-(CC)-Ph 291. 3-acetyl-5-(isopropyl)-Ph292. 3-acetyl-5-(SO2NH2)-Ph 293. 3-acetyl-5-(CO-4-morpholine)-Ph 294.3-isopropyl-5-(1-methyltetrazol-5-yl)-Ph 295.3-SO2NH2-5-(1-methyltetrazol-5-yl)-Ph 296. 3,5-di(OMe)-Ph 297.3,4,5-tri(Ome)-Ph R⁵ or R¹⁷ 1. H 2. 4-F-Ph 3. 2-F-Ph 4. 2,4-diF-Ph 5.4-Cl-Ph 6. 2-Cl-Ph 7. 2,4-diCl-Ph 8. 3-OCH3-Ph 9. 2-thienyl 10.3-thienyl 11. 2-furanyl 12. 3-furanyl 13. 2-pyridyl 14. 3-pyridyl 15.4-pyridyl 16. 3-indolyl 17. 5-indolyl 18. 5-indazolyl 19.5-benzimidazolyl 20. 5-benzothiazolyl 21. 5-benzoxazolyl

Utility

The utility of the compounds in accordance with the present invention asmodulators of chemokine receptor activity may be demonstrated bymethodology known in the art, such as the assays for CCR-2 and CCR-3ligand binding, as disclosed by Ponath et al., J. Exp. Med., 183,2437-2448 (1996) and Uguccioni et al., J. Clin. Invest., 100, 1137-1143(1997). Cell lines for expressing the receptor of interest include thosenaturally expressing the chemokine receptor, such as EOL-3 or THP-1,those induced to express the chemokine receptor by the addition ofchemical or protein agents, such as HL-60 or AML14.3D10 cells treatedwith, for example, butyric acid with interleukin-5 present, or a cellengineered to express a recombinant chemokine receptor, such as CHO orHEK-293. Finally, blood or tissue cells, for example human peripheralblood eosinophils, isolated using methods as described by Hansel et al.,J. Immunol. Methods, 145, 105-110 (1991), can be utilized in suchassays. In particular, the compound of the present invention haveactivity in binding to the CCR-3 receptor in the aforementioned assays.As used herein, “activity” is intended to mean a compound demonstratingan IC50 of 10 μM or lower in concentration when measured in theaforementioned assays. Such a result is indicative of the intrinsicactivity of the compounds as modulators of chemokine receptor activity.A general binding protocol is described below.

CCR³-Receptor Binding Protocol

Millipore filter plates (#MABVN1250) are treated with 5 μg/ml protaminein phosphate buffered saline, pH 7.2, for ten minutes at roomtemperature. Plates are washed three times with phosphate bufferedsaline and incubated with phosphate buffered saline for thirty minutesat room temperature. For binding, 50 μl of binding buffer (0.5% bovineserum albumen, 20 mM HEPES buffer and 5 mM magnesium chloride in RPMI1640 media) with or without a test concentration of a compound presentat a known concentration is combined with 50 μl of 125-I labeled humaneotaxin (to give a final concentration of 150 pM radioligand) and 50 μlof cell suspension in binding buffer containing 5×10⁵ total cells. Cellsused for such binding assays can include cell lines transfected with agene expressing CCR³ such as that described by Daugherty et al. (1996),isolated human eosinophils such as described by Hansel et al. (1991) orthe AML14.3D10 cell line after differentiation with butyric acid asdescribed by Tiffany et al. (1998). The mixture of compound, cells andradioligand are incubated at room temperature for thirty minutes. Platesare placed onto a vacuum manifold, vacuum applied, and plates washedthree times with binding buffer with 0.5M NaCl added. The plastic skirtis removed from the plate, the plate allowed to air dry, the wells punchout and CPM counted. The percent inhibition of binding is calculatedusing the total count obtained in the absence of any competing compoundor chemokine ligand and the background binding determined by addition of100 nM eotaxin in place of the test compound.

The utility of the compounds in accordance with the present invention asinhibitors of the migration of eosinophils or cell lines expressing thechemokine receptors may be demonstrated by methodology known in the art,such as the chemotaxis assay disclosed by Bacon et al., Brit. J.Pharmacol., 95, 966-974 (1988). In particular, the compound of thepresent invention have activity in inhibition of the migration ofeosinophils in the aforementioned assays. As used herein, “activity” isintended to mean a compound demonstrating an IC50 of 10 μM or lower inconcentration when measured in the aforementioned assays. Such a resultis indicative of the intrinsic activity of the compounds as modulatorsof chemokine receptor activity. A human eosinophil chemotaxis assayprotocol is described below.

Human Eosinophil Chemotaxis Assay

Neuroprobe MBA96 96-well chemotaxis chambers with Neuroprobepolyvinylpyrrolidone-free polycarbonate PFD5 5-micron filters in placeare warmed in a 37° C. incubator prior to assay. Freshly isolated humaneosinophils, isolated according to a method such as that described byHansel et al. (1991), are suspended in RPMI 1640 with 0.1% bovine serumalbumin at 1×10⁶ cells/ml and warmed in a 37° C. incubator prior toassay. A 20 nM solution of human eotaxin in RPMI 1640 with 0.1% bovineserum albumin is warmed in a 37° C. incubator prior to assay. Theeosinophil suspension and the 20 nM eotaxin solution are each mixed 1:1with prewarmed RPMI 1640 with 0.1% bovine serum albumin with or withouta dilution of a test compound that is at two fold the desired finalconcentration. These mixtures are warmed in a 37° C. incubator prior toassay. The filter is separated from the prewarmed Neuroprobe chemotaxischamber and the eotaxin/compound mixture is placed into a PolyfiltronicsMPC 96 well plate that has been placed in the bottom part of the NeuroProbe chemotaxis chamber. The approximate volume is 370 microliters andthere should be a positive meniscus after dispensing. The filter isreplaced above the 96 well plate, the rubber gasket is attached to thebottom of the upper chamber, and the chamber assembled. A 200 μl volumeof the cell suspension/compound mixture is added to the appropriatewells of the upper chamber. The upper chamber is covered with a platesealer, and the assembled unit placed in a 37° C. incubator for 45minutes. After incubation, the plate sealer is removed and all remainingcell suspension is aspirated off. The chamber is disassembled and, whileholding the filter by the sides at a 90-degree angle, unmigrated cellsare washed away using a gentle stream of phosphate buffered salinedispensed from a squirt bottle and then the filter wiped with a rubbertipped squeegee. The filter is allowed to completely dry and immersedcompletely in Wright Giemsa stain for 30-45 seconds. The filter isrinsed with distilled water for 7 minutes, rinsed once with waterbriefly, and allowed to dry. Migrated cells are enumerated bymicroscopy.

Mammalian chemokine receptors provide a target for interfering with orpromoting immune cell function in a mammal, such as a human. Compoundsthat inhibit or promote chemokine receptor function are particularlyuseful for modulating immune cell function for therapeutic purposes.Accordingly, the present invention is directed to compounds which areuseful in the prevention and/or treatment of a wide variety ofinflammatory, infectious, and immunoregulatory disorders and diseases,including asthma and allergic diseases, infection by pathogenic microbes(which, by definition, includes viruses), as well as autoimmunepathologies such as the rheumatoid arthritis and atherosclerosis.

For example, an instant compound which inhibits one or more functions ofa mammalian chemokine receptor (e.g., a human chemokine receptor) may beadministered to inhibit (i.e., reduce or prevent) inflammation orinfectious disease. As a result, one or more inflammatory process, suchas leukocyte emigration, adhesion, chemotaxis, exocytosis (e.g., ofenzymes, histamine) or inflammatory mediator release, is inhibited. Forexample, eosinophilic infiltration to inflammatory sites (e.g., inasthma or allergic rhinitis) can be inhibited according to the presentmethod. In particular, the compound of the following examples hasactivity in blocking the migration of cells expressing the CCR-3receptor using the appropriate chemokines in the aforementioned assays.As used herein, “activity” is intended to mean a compound demonstratingan IC50 of 10 μM or lower in concentration when measured in theaforementioned assays. Such a result is also indicative of the intrinsicactivity of the compounds as modulators of chemokine receptor activity.

Similarly, an instant compound which promotes one or more functions ofthe mammalian chemokine receptor (e.g., a human chemokine) asadministered to stimulate (induce or enhance) an immune or inflammatoryresponse, such as leukocyte emigration, adhesion, chemotaxis, exocytosis(e.g., of enzymes, histamine) or inflammatory mediator release,resulting in the beneficial stimulation of inflammatory processes. Forexample, eosinophils can be recruited to combat parasitic infections. Inaddition, treatment of the aforementioned inflammatory, allergic andautoimmune diseases can also be contemplated for an instant compoundwhich promotes one or more functions of the mammalian chemokine receptorif one contemplates the delivery of sufficient compound to cause theloss of receptor expression on cells through the induction of chemokinereceptor internalization or the delivery of compound in a manner thatresults in the misdirection of the migration of cells.

In addition to primates, such as humans, a variety of other mammals canbe treated according to the method of the present invention. Forinstance, mammals, including but not limited to, cows, sheep, goats,horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine,canine, feline, rodent or murine species can be treated. However, themethod can also be practiced in other species, such as avian species.The subject treated in the methods above is a mammal, male or female, inwhom modulation of chemokine receptor activity is desired. “Modulation”as used herein is intended to encompass antagonism, agonism, partialantagonism and/or partial agonism.

Diseases or conditions of human or other species which can be treatedwith inhibitors of chemokine receptor function, include, but are notlimited to: inflammatory or allergic diseases and conditions, includingrespiratory allergic diseases such as asthma, allergic rhinitis,hypersensitivity lung diseases, hypersensitivity pneumonitis,eosinophilic cellulitis (e.g., Well's syndrome), eosinophilic pneumonias(e.g., Loeffler's syndrome, chronic eosinophilic pneumonia),eosinophilic fasciitis (e.g., Shulman's syndrome), delayed-typehypersensitivity, interstitial lung diseases (ILD) (e.g., idiopathicpulmonary fibrosis, or ILD associated with rheumatoid arthritis,systemic lupus erythematosus, ankylosing spondylitis, systemicsclerosis, Sjogren's syndrome, polymyositis or dermatomyositis);systemic anaphylaxis or hypersensitivity responses, drug allergies(e.g., to penicillin, cephalosporins), eosinophilia-myalgia syndrome dueto the ingestion of contaminated tryptophan, insect sting allergies;autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis,multiple sclerosis, systemic lupus erythematosus, myasthenia gravis,juvenile onset diabetes; glomerulonephritis, autoimmune thyroiditis,Behcet's disease; graft rejection (e.g., in transplantation), includingallograft rejection or graft-versus-host disease; inflammatory boweldiseases, such as Crohn's disease and ulcerative colitis;spondyloarthropathies; scleroderma; psoriasis (including T-cell mediatedpsoriasis) and inflammatory dermatoses such as an dermatitis, eczema,atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis(e.g., necrotizing, cutaneous, and hypersensitivity vasculitis);eosinophilic myositis, eosinophilic fasciitis; cancers with leukocyteinfiltration of the skin or organs. Other diseases or conditions inwhich undesirable inflammatory responses are to be inhibited can betreated, including, but not limited to, reperfusion injury,atherosclerosis, certain hematologic malignancies, cytokine-inducedtoxicity (e.g., septic shock, endotoxic shock), polymyositis,dermatomyositis. Infectious diseases or conditions of human or otherspecies which can be treated with inhibitors of chemokine receptorfunction, include, but are not limited to, HIV.

Diseases or conditions of humans or other species which can be treatedwith promoters of chemokine receptor function, include, but are notlimited to: immunosuppression, such as that in individuals withimmunodeficiency syndromes such as AIDS or other viral infections,individuals undergoing radiation therapy, chemotherapy, therapy forautoimmune disease or drug therapy (e.g., corticosteroid therapy), whichcauses immunosuppression; immunosuppression due to congenital deficiencyin receptor function or other causes; and infections diseases, such asparasitic diseases, including, but not limited to helminth infections,such as nematodes (round worms); (Trichuriasis, Enterobiasis,Ascariasis, Hookworm, Strongyloidiasis, Trichinosis, filariasis);trematodes (flukes) (Schistosomiasis, Clonorchiasis), cestodes (tapeworms) (Echinococcosis, Taeniasis saginata, Cysticercosis); visceralworms, visceral larva migraines (e.g., Toxocara), eosinophilicgastroenteritis (e.g., Anisaki sp., Phocanema sp.), cutaneous larvamigraines (Ancylostona braziliense, Ancylostoma caninum). The compoundsof the present invention are accordingly useful in the prevention andtreatment of a wide variety of inflammatory, infectious andimmunoregulatory disorders and diseases. In addition, treatment of theaforementioned inflammatory, allergic and autoimmune diseases can alsobe contemplated for promoters of chemokine receptor function if onecontemplates the delivery of sufficient compound to cause the loss ofreceptor expression on cells through the induction of chemokine receptorinternalization or delivery of compound in a manner that results in themisdirection of the migration of cells.

In another aspect, the instant invention may be used to evaluate theputative specific agonists or antagonists of a G protein coupledreceptor. The present invention is directed to the use of thesecompounds in the preparation and execution of screening assays forcompounds that modulate the activity of chemokine receptors.Furthermore, the compounds of this invention are useful in establishingor determining the binding site of other compounds to chemokinereceptors, e.g., by competitive inhibition or as a reference in an assayto compare its known activity to a compound with an unknown activity.When developing new assays or protocols, compounds according to thepresent invention could be used to test their effectiveness.Specifically, such compounds may be provided in a commercial kit, forexample, for use in pharmaceutical research involving the aforementioneddiseases. The compounds of the instant invention are also useful for theevaluation of putative specific modulators of the chemokine receptors.In addition, one could utilize compounds of this invention to examinethe specificity of G protein coupled receptors that are not thought tobe chemokine receptors, either by serving as examples of compounds whichdo not bind or as structural variants of compounds active on thesereceptors which may help define specific sites of interaction.

Combined therapy to prevent and treat inflammatory, infectious andimmunoregulatory disorders and diseases, including asthma and allergicdiseases, as well as autoimmune pathologies such as rheumatoid arthritisand atherosclerosis, and those pathologies noted above is illustrated bythe combination of the compounds of this invention and other compoundswhich are known for such utilities. For example, in the treatment orprevention of inflammation, the present compounds may be used inconjunction with an anti-inflammatory or analgesic agent such as anopiate agonist, a lipoxygenase inhibitor, a cyclooxygenase-2 inhibitor,an interleukin inhibitor, such as an interleukin-1 inhibitor, a tumornecrosis factor inhibitor, an NMDA antagonist, an inhibitor or nitricoxide or an inhibitor of the synthesis of nitric oxide, a non-steroidalanti-inflammatory agent, a phosphodiesterase inhibitor, or acytokine-suppressing anti-inflammatory agent, for example with acompound such as acetaminophen, aspirin, codeine, fentaynl, ibuprofen,indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, asteroidal analgesic, sufentanyl, sunlindac, interferon alpha and thelike. Similarly, the instant compounds may be administered with a painreliever; a potentiator such as caffeine, an H2-antagonist, simethicone,aluminum or magnesium hydroxide; a decongestant such as phenylephrine,phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine,naphazoline, xylometazoline, propylhexedrine, or levodesoxy-ephedrine;and antitussive such as codeine, hydrocodone, caramiphen,carbetapentane, or dextramethorphan; a diuretic; and a sedating ornon-sedating antihistamine. Likewise, compounds of the present inventionmay be used in combination with other drugs that are used in thetreatment/prevention/suppression or amelioration of the diseases orconditions for which compound of the present invention are useful. Suchother drugs may be administered, by a route and in an amount commonlyused therefore, contemporaneously or sequentially with a compound of thepresent invention. When a compound of the present invention is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound ofthe present invention is preferred. Accordingly, the pharmaceuticalcompositions of the present invention include those that also containone or more other active ingredients, in addition to a compound of thepresent invention. Examples of other active ingredients that may becombined with a compound of the present invention, either administeredseparately or in the same pharmaceutical compositions, include, but arenot limited to: (a) integrin antagonists such as those for selecting,ICAMs and VLA-4; (b) steroids such as beclomethasone,methylprednisolone, betamethasone, prednisone, dexamethasone, andhydrocortisone; (c) immunosuppressants such as cyclosporin, tacrolimus,rapamycin and other FK-506 type immunosuppressants; (d) antihistamines(H1-histamine antagonists) such as bromopheniramine, chlorpheniramine,dexchlorpheniramine, triprolidine, clemastine, diphenhydramine,diphenylpyraline, tripelennamine, hydroxyzine, methdilazine,promethazine, trimeprazine, azatadine, cyproheptadine, antazoline,pheniramine pyrilamine, astemizole, terfenadine, loratadine, cetirizine,fexofenadine, descarboethoxyloratadine, and the like; (e) non-steroidalanti-asthmatics such as b2-agonists (terbutaline, metaproterenol,fenoterol, isoetharine, albuteral, bitolterol, and pirbuterol),theophylline, cromolyn sodium, atropine, ipratropium bromide,leukotriene antagonists (zafirlukast, montelukast, pranlukast,iralukast, pobilukast, SKB-102,203), leukotriene biosynthesis inhibitors(zileuton, BAY-1005); (f) non-steroidal antiinflammatory agents (NSAIDs)such as propionic acid derivatives (alminoprofen, benxaprofen, bucloxicacid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen,ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin,pirprofen, pranoprofen, suprofen, tiaprofenic acid, and tioxaprofen),acetic acid derivatives (indomethacin, acemetacin, alclofenac, clidanac,diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac,isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin, andzomepirac), fenamic acid derivatives (flufenamic acid, meclofenamicacid, mefenamic acid, niflumic acid and tolfenamic acid),biphenylcarboxylic acid derivatives (diflunisal and flufenisal), oxicams(isoxicam, piroxicam, sudoxicam and tenoxican), salicylates (acetylsalicylic acid, sulfasalazine) and the pyrazolones (apazone,bezpiperylon, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone);(g) cyclooxygenase-2 (COX-2) inhibitors; (h) inhibitors ofphosphodiesterase type IV (PDE-IV); (I) other antagonists of thechemokine receptors; (j) cholesterol lowering agents such as HMG-COAreductase inhibitors (lovastatin, simvastatin and pravastatin,fluvastatin, atorvsatatin, and other statins), sequestrants(cholestyramine and colestipol), nicotonic acid, fenofibric acidderivatives (gemfibrozil, clofibrat, fenofibrate and benzafibrate), andprobucol; (k) anti-diabetic agents such as insulin, sulfonylureas,biguamides (metformin), a-glucosidase inhibitors (acarbose) andglitazones (troglitazone ad pioglitazone); (l) preparations ofinterferons (interferon alpha-2a, interferon-2B, interferon alpha-N3,interferon beta-1a, interferon beta-1b, interferon gamma-1b); (m)antiviral compounds such as efavirenz, nevirapine, indinavir,ganciclovir, lamivudine, famciclovir, and zalcitabine; (o) othercompound such as 5-aminosalicylic acid an prodrugs thereof,antimetabolites such as azathioprine and 6-mercaptopurine, and cytotoxiccancer chemotherapeutic agents. The weight ratio of the compound of thepresent invention to the second active ingredient may be varied and willdepend upon the effective doses of each ingredient. Generally, aneffective dose of each will be used. Thus, for example, when a compoundof the present invention is combined with an NSAID the weight ratio ofthe compound of the present invention to the NSAID will generally rangefrom about 1000:1 to about 1:1000, preferably about 200:1 to about1:200. Combinations of a compound of the present invention and otheractive ingredients will generally also be within the aforementionedrange, but in each case, an effective dose of each active ingredientshould be used.

The compounds are administered to a mammal in a therapeuticallyeffective amount. By “therapeutically effective amount” it is meant anamount of a compound of Formula I that, when administered alone or incombination with an additional therapeutic agent to a mammal, iseffective to prevent or ameliorate the thromboembolic disease conditionor the progression of the disease.

Dosage and Formulation

The compounds of this invention can be administered in such oral dosageforms as tablets, capsules (each of which includes sustained release ortimed release formulations), pills, powders, granules, elixirs,tinctures, suspensions, syrups, and emulsions. They may also beadministered in intravenous (bolus or infusion), intraperitoneal,subcutaneous, or intramuscular form, all using dosage forms well knownto those of ordinary skill in the pharmaceutical arts. They can beadministered alone, but generally will be administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient, and theeffect desired. A physician or veterinarian can determine and prescribethe effective amount of the drug required to prevent, counter, or arrestthe progress of the thromboembolic disorder.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to 1000 mg/kg of body weight, preferably between about 0.01to 100 mg/kg of body weight per day, and most preferably between about1.0 to 20 mg/kg/day. Intravenously, the most preferred doses will rangefrom about 1 to about 10 mg/kg/minute during a constant rate infusion.Compounds of this invention may be administered in a single daily dose,or the total daily dosage may be administered in divided doses of two,three, or four times daily.

Compounds of this invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal routes,using transdermal skin patches. When administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittent throughout the dosage regimen.

The compounds are typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, that is, oral tablets, capsules,elixirs, syrups and the like, and consistent with conventionalpharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl callulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 100 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.5-95% by weight based on the total weight of the composition.

Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfite, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also used are citric acid and its saltsand sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propyl-paraben,and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field.

Representative useful pharmaceutical dosage-forms for administration ofthe compounds of this invention can be illustrated as follows:

Capsules

A large number of unit capsules can be prepared by filling standardtwo-piece hard gelatin capsules each with 100 milligrams of powderedactive ingredient, 150 milligrams of lactose, 50 milligrams ofcellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestable oil such as soybean oil,cottonseed oil or olive oil may be prepared and injected by means of apositive displacement pump into gelatin to form soft gelatin capsulescontaining 100 milligrams of the active ingredient. The capsules shouldbe washed and dried.

Tablets

Tablets may be prepared by conventional procedures so that the dosageunit is 100 milligrams of active ingredient, 0.2 milligrams of colloidalsilicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams ofmicrocrystalline cellulose, 11 milligrams of starch and 98.8 milligramsof lactose. Appropriate coatings may be applied to increase palatabilityor delay absorption.

Injectable

A parenteral composition suitable for administration by injection may beprepared by stirring 1.5% by weight of active ingredient in 10% byvolume propylene glycol and water. The solution should be made isotonicwith sodium chloride and sterilized.

Suspension

An aqueous suspension can be prepared for oral administration so thateach 5 mL contain 100 mg of finely divided active ingredient, 200 mg ofsodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g ofsorbitol solution, U.S.P., and 0.025 mL of vanillin.

Where the compounds of this invention are combined with otheranticoagulant agents, for example, a daily dosage may be about 0.1 to100 milligrams of the compound of Formula I and about 1 to 7.5milligrams of the second anticoagulant, per kilogram of patient bodyweight. For a tablet dosage form, the compounds of this inventiongenerally may be present in an amount of about 5 to 10 milligrams perdosage unit, and the second anti-coagulant in an amount of about 1 to 5milligrams per dosage unit.

Where two or more of the foregoing second therapeutic agents areadministered with the compound of Formula I, generally the amount ofeach component in a typical daily dosage and typical dosage form may bereduced relative to the usual dosage of the agent when administeredalone, in view of the additive or synergistic effect of the therapeuticagents when administered in combination.

Particularly when provided as a single dosage unit, the potential existsfor a chemical interaction between the combined active ingredients. Forthis reason, when the compound of Formula I and a second therapeuticagent are combined in a single dosage unit they are formulated such thatalthough the active ingredients are combined in a single dosage unit,the physical contact between the active ingredients is minimized (thatis, reduced). For example, one active ingredient may be enteric coated.By enteric coating one of the active ingredients, it is possible notonly to minimize the contact between the combined active ingredients,but also, it is possible to control the release of one of thesecomponents in the gastrointestinal tract such that one of thesecomponents is not released in the stomach but rather is released in theintestines. One of the active ingredients may also be coated with amaterial which effects a sustained-release throughout thegastrointestinal tract and also serves to minimize physical contactbetween the combined active ingredients. Furthermore, thesustained-released component can be additionally enteric coated suchthat the release of this component occurs only in the intestine. Stillanother approach would involve the formulation of a combination productin which the one component is coated with a sustained and/or entericrelease polymer, and the other component is also coated with a polymersuch as a low-viscosity grade of hydroxypropyl methylcellulose (HPMC) orother appropriate materials as known in the art, in order to furtherseparate the active components. The polymer coating serves to form anadditional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

As will be apparent to one skilled in the art, numerous modificationsand variations of the present invention are possible in light of theabove teachings. It is therefore to be understood that within the scopeof the appended claims, the invention may be practiced otherwise than asspecifically described herein.

1. A compound of formula (I):

or stereoisomers or pharmaceutically acceptable salts thereof, wherein:Ring D is a 6-membered ring heterocycle wherein B is NR¹⁷ with theheterocycle further containing at least one carbonyl or sulfonyltherein; R⁴ is selected from H, R⁵ and R¹³; R¹⁷ is selected from H, R⁵and R¹⁸; with the proviso that Ring D contains at least one R⁵; Z isselected from O, S, NR^(1a), C(CN)₂, CH(NO₂), and CHCN; R^(1a) isselected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, CONR^(1b)R^(1b), OR^(1b),CN, NO₂, and (CH₂)_(w)phenyl; R^(1b) is independently selected from H,C₁₋₃ alkyl, C₃₋₆ cycloalkyl, and phenyl; E is—(CR⁷CR⁸)—(CR⁹R¹⁰)_(v)—(CR¹¹R¹²), —(C═O)—(CR⁹R¹⁰)_(v)—(CR¹¹R¹²)—,—(SO₂)—(CR⁹R¹⁰)_(v)—(CR¹¹R¹²)—,

Ring A is a C₃₋₈ carbocyclic residue; R¹ and R² are independentlyselected from H, C₁₋₈ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, and a(CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(a); R^(a),at each occurrence, is independently selected from C₁₋₄ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F,(CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(b)R^(b), (CH₂)_(r)OH,(CH₂)_(r)OR^(c), (CH₂)_(r)SH, (CH₂)_(r)SR^(c), (CH₂)_(r)C(O)R^(b),(CH₂)_(r)C(O)NR^(b)R^(b), (CH₂)_(r)NR^(b)C(O)R^(b), (CH₂)_(r)C(O)OR^(b),(CH₂)_(r)OC(O)R^(c), (CH₂)_(r)CH(═NR^(b))NR^(b)R^(b),(CH₂)_(r)NHC(═NR^(b))NR^(b)R^(b), (CH₂)_(r)S(O)_(p)R^(c),(CH₂)_(r)S(O)₂NR^(b)R^(b), (CH₂)_(r)NR^(b)S(O)₂R^(c), and(CH₂)_(r)phenyl; R^(b), at each occurrence, is independently selectedfrom H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and phenyl; R^(c), at eachoccurrence, is independently selected from C₁₋₆ alkyl, C₃₋₆ cycloalkyl,and phenyl; R³ is selected from a (CR^(3a)R^(3b))_(r)—C₃₋₈ carbocyclicresidue substituted with 0-5 R¹⁵; and a (CR^(3a)R^(3b))_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R¹⁵; R^(3a) and R^(3b), at eachoccurrence, are independently selected from H, C₁₋₆alkyl, (CH₂)_(r)C₃₋₆cycloalkyl, and phenyl; R⁵ is selected from a (CR^(5a)R^(5b))_(t)—C₃₋₁₀carbocyclic residue substituted with 0-5 R¹⁶ and a(CR^(5a)R^(5b))_(t)-5-10 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R¹⁶; R^(5a)and R^(5b), at each occurrence, are selected from H, C₁₋₆ alkyl,(CH₂)_(r)C₃₋₆ cycloalkyl, and phenyl; R⁷, is selected from H, C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(q)OH, (CH₂)_(q)SH,(CH₂)_(q)OR^(7d), (CH₂)_(q)SR^(7d), (CH₂)_(q)NR^(7a)R^(7a),(CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(7b), (CH₂)_(r)C(O)NR^(7a)R^(7a),(CH₂)_(q)NR^(7a)C(O)R^(7a), (CH₂)_(q)NR^(7a)C(O)H, (CH₂)_(r)C(O)OR^(7b),(CH₂)_(q)OC(O)R^(7b), (CH₂)_(q)S(O)_(p)R^(7b),(CH₂)_(q)S(O)₂NR^(7a)R^(7a), (CH₂)_(q)NR^(7a)S(O)₂R^(7b), C₁₋₆haloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3R^(7c), and a (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-2 R^(7c);R^(7a), at each occurrence, is independently selected from H, C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, a(CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(7e), and a(CH₂)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(7e); R^(7b), at eachoccurrence, is independently selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2R^(7e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R^(7e);R^(7c), at each occurrence, is independently selected from C₁₋₆ alkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F,(CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(7f)R^(7f), (CH₂)_(r)OH,(CH₂)_(r)OC₁₋₄ alkyl, (CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH,(CH₂)_(r)C(O)R^(7b), (CH₂)_(r)C(O)NR^(7f)R^(7f),(CH₂)_(r)NR^(7f)C(O)R^(7a), (CH₂)_(r)C(O)OC₁₋₄ alkyl,(CH₂)_(r)OC(O)R^(7b), (CH₂)_(r)C(═NR^(7f))NR^(7f)R^(7f),(CH₂)_(r)S(O)_(p)R^(7b), (CH₂)_(r)NHC(═NR^(7f))NR^(7f)R^(7f),(CH₂)_(r)S(O)₂NR^(7f)R^(7f), (CH₂)_(r)NR^(7f)S(O)₂R^(7b), and(CH₂)_(r)phenyl substituted with 0-3 R^(7e); R^(7d), at each occurrence,is independently selected from methyl, CF₃ C₂₋₆ alkyl substituted with0-3 R^(7e), alkenyl, alkynyl, and a C₃₋₁₀ carbocyclic residuesubstituted with 0-3 R^(7c); R^(7e), at each occurrence, isindependently selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl,OH, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(7f)R^(7f), and(CH₂)_(r)phenyl; R^(7f), at each occurrence, is independently selectedfrom H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; R⁸ is selected from H, C₁₋₆alkyl, C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3 R^(8a);R^(8a), at each occurrence, is independently selected from C₁₋₆ alkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(8f)R^(8f), and (CH₂)_(r)phenyl; alternatively, R⁷ and R⁸join to form C₃₋₇ cycloalkyl, or ═NR^(8b); R^(8b) is selected from H,C₁₋₆ alkyl, C₃₋₆ cycloalkyl, OH, CN, and (CH₂)_(r)-phenyl; R^(8f), ateach occurrence, is independently selected from H, C₁₋₆ alkyl, and C₃₋₆cycloalkyl; R⁹, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, F, Cl, Br, I, NO₂, CN, (CHR′)_(r)OH, (CHR′)_(r)OR^(9d),(CHR′)_(r)SR^(9d), (CHR′)_(r)NR^(9a)R^(9a), (CHR′)_(r)C(O)OH,(CHR′)_(r)C(O)R^(9b), (CHR′)_(r)C(O)NR^(9a)R^(9a),(CHR′)_(r)NR^(9a)C(O)R^(9b), (CHR′)_(r)NR^(9a)C(O)H,(CHR′)_(r)C(O)OR^(9b), (CHR′)_(r)OC(O)R^(9b),(CHR′)_(r)OC(O)NR^(9a)R^(9a), (CHR′)_(r)NR^(9a)C(O)OR^(9b),(CHR′)_(r)S(O)_(p)R^(9b), (CHR′)_(r)S(O)₂NR^(9a)R^(9a),(CHR′)_(r)NR^(9a)S(O)₂R^(9b), C₁₋₆ haloalkyl, a (CHR′)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-5 R^(9c), and a (CHR′)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(9c); R^(9a), at each occurrence, isindependently selected from H, C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a(CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(9e), and a(CH₂)_(r)-4-10 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(9e); alternatively,two R^(9a)s, along with the N to which they are attached, join to form a5-6 membered heterocyclic system containing 1-2 heteroatoms selectedfrom NR^(9g), O, and S and optionally fused with a benzene ring or a6-membered aromatic heterocycle; R^(9b), at each occurrence, isindependently selected from C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a(CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2 R^(9e), and a(CH₂)_(r)-4-6 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(9e); R^(9c), at eachoccurrence, is independently selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, (CF₂)_(r)CF₃, NO₂,CN, (CH₂)_(r)NR^(9f)R^(9f), (CH₂)_(r)OH, (CH₂)_(r)OR^(9b),(CH₂)_(r)SR^(9b), (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(9b),(CH₂)_(r)C(O)NR^(9f)R^(9f), (CH₂)_(r)NR^(9f)C(O)R^(9b),(CH₂)_(r)C(O)OR^(9b), (CH₂)_(r)OC(O)R^(9b),(CH₂)_(r)C(═NR^(9f))NR^(9f)R^(9f), (CH₂)_(r)S(O)_(p)R^(9b),(CH₂)_(r)NHC(═NR^(9f))NR^(9f)R^(9f), (CH₂)_(r)S(O)₂NR^(9f)R^(9f),(CH₂)_(r)NR^(9f)S(O)₂R^(9b), and (CH₂)_(r)phenyl substituted with 0-3R^(9e); R^(9d), at each occurrence, is independently selected frommethyl, CF₃, C₂₋₆ alkyl residue substituted with 0-3 R^(9e), C₃₋₆alkenyl, C₃₋₆ alkynyl, a C₃₋₁₀ carbocyclic residue substituted with 0-3R^(9c), and a 5-6 membered heterocyclic system containing 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R^(9c); R^(9e), at each occurrence, isindependently selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,(CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(9f)R^(9f), and (CH₂)_(r)phenyl, wherein the phenyl on the(CH₂)_(r)phenyl is substituted with 0-5 substituents selected from F,Cl, Br, I, NO₂, C₁₋₆alkyl, OH, and NR^(9f)R^(9f); R^(9f), at eachoccurrence, is independently selected from H, C₁₋₆ alkyl, and C₃₋₆cycloalkyl; R^(9g) is selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,(CH₂)_(r)phenyl, C(O)R^(9f), C(O)OR^(9h), and SO₂R^(9h); R^(9h), at eachoccurrence, is independently selected from C₁₋₆ alkyl, and C₃₋₆cycloalkyl; R¹⁰, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, F, Cl, Br, I, NO₂, CN, (CHR′)_(r)OH, (CH₂)_(r)OR^(10d),(CH₂)_(r)SR^(10d), (CH₂)_(r)NR^(10a)R^(10a), (CH₂)_(r)C(O)OH,(CH₂)_(r)C(O)R^(10b), (CH₂)_(r)C(O)NR^(10a)R^(10a),(CH₂)_(r)NR^(10a)C(O)R^(10a), (CH₂)_(r)NR^(10a)C(O)H,(CH₂)_(r)C(O)OR^(10b), (CH₂)_(r)OC(O)R^(10b),(CH₂)_(r)OC(O)NR^(10a)R^(10a), (CH₂)_(r)NR^(10a)C(O)OR^(10b),(CH₂)_(r)S(O)_(p)R^(10b), (CH₂)_(r)S(O)₂NR^(10a)R^(10a),(CH₂)_(r)NR^(10a)S(O)₂R^(10b), C₁₋₆ haloalkyl, a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-5 R^(10c), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(10c); R^(10a), at each occurrence, isindependently selected from H, C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a(CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(10e), and a(CH₂)_(r)-4-10 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(10e); alternatively,two R^(10a)s, along with the N to which they are attached, join to forma 5-6 membered heterocyclic system containing 1-2 heteroatoms selectedfrom NR^(10g), O, and S and optionally fused with a benzene ring or a6-membered aromatic heterocycle; R^(10b), at each occurrence, isindependently selected from C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a(CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2 R^(10e), and a(CH₂)_(r)-4-6 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(10e); R^(10c), ateach occurrence, is independently selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F,(CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(10f)R^(10f), (CH₂)_(r)OH,(CH₂)_(r)OR^(10b), (CH₂)_(r)SR^(10b), (CH₂)_(r)C(O)OH,(CH₂)_(r)C(O)R^(10b), (CH₂)_(r)C(O)NR^(10f)R^(10f),(CH₂)_(r)NR^(10f)C(O)R^(10a), (CH₂)_(r)C(O)OR^(10b),(CH₂)_(r)OC(O)R^(10b), (CH₂)_(r)C(═NR^(10f))NR^(10f)R^(10f),(CH₂)_(r)S(O)_(p)R^(10b), (CH₂)_(r)NHC(═NR^(10f))NR^(10f)R^(10f),(CH₂)_(r)S(O)₂NR^(10f)R^(10f), (CH₂)_(r)NR^(10f)S(O)₂R^(10b), and(CH₂)_(r)phenyl substituted with 0-3 R^(10e); R^(10d), at eachoccurrence, is independently selected from methyl, CF₃, C₂₋₆ alkylsubstituted with 0-3 R^(10e), C₃₋₆ alkenyl, C₃₋₆ alkynyl, and a C₃₋₁₀carbocyclic residue substituted with 0-3 R^(10c); R^(10e), at eachoccurrence, is independently selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(10f)R^(10f), and (CH₂)_(r)phenyl; R^(10f), at eachoccurrence, is independently selected from H, C₁₋₆ alkyl, and C₃₋₆cycloalkyl; R^(10g) is selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,(CH₂)_(r)phenyl, C(O)R^(10f), SO₂R^(10h), and C(O)O R^(10h); R^(10h), ateach occurrence, is independently selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl; alternatively, R⁹ and R¹⁰ join to form ═O, a C₃₋₁₀cycloalkyl, a 5-6-membered lactone or lactam, or a 4-6-memberedsaturated heterocycle containing 1-2 heteroatoms selected from O, S, andNR^(10g) and optionally fused with a benzene ring or a 6-memberedaromatic heterocycle; R¹¹, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CR′R′)_(q)OH, (CH₂)_(q)SH, (CR′R′)_(q)OR^(11d),(CHR′)_(q)SR^(11d), (CR′R′)_(q)NR^(11a)R^(11a), (CHR′)_(r)C(O)OH,(CHR′)_(r)C(O)R^(11b), (CHR′)_(r)C(O)NR^(11a)R^(11a),(CHR′)_(q)NR^(11a)C(O)R^(11a), (CHR′)_(q)OC(O)NR^(11a)R^(11a),(CHR′)_(q)NR^(11a)C(O)OR^(11b), (CHR′)_(q)NR^(11a)C(O)NHR^(11a),(CHR′)_(r)C(O)OR^(11b), (CHR′)_(q)OC(O)R^(11b),(CHR′)_(q)S(O)_(p)R^(11b), (CHR′)_(q)S(O)₂NR^(11a)R^(11a),(CHR′)_(q)NR^(11a)S(O)₂R^(11b), C₁₋₆ haloalkyl, a (CHR′)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-5 R^(11c), and a (R′R¹⁷)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(11c); R^(11a), at each occurrence, isindependently selected from H, C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a(CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(11e), and a(CH₂)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(11e); alternatively,two R^(11a)s, along with the N to which they are attached, join to forma 5-6 membered heterocyclic system containing 1-2 heteroatoms selectedfrom NR^(11g), O, and S and optionally fused with a benzene ring or a6-membered aromatic heterocycle; R^(11b), at each occurrence, isindependently selected from C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a(CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2 R^(11e), and a(CH₂)_(r)-4-6 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(11e); R^(11c), ateach occurrence, is independently selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F,(CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(11f)R^(11f), (CH₂)_(r)OH,(CH₂)_(r)OC₁₋₄ alkyl, (CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH,(CH₂)_(r)C(O)R^(11b), (CH₂)_(r)C(O)NR^(11f)R^(11f),(CH₂)_(r)NR^(11f)C(O)R^(11a), (CH₂)_(r)C(O)OC₁₋₄ alkyl,(CH₂)_(r)OC(O)R^(11b), (CH₂)_(r)C(═NR^(11f))NR^(11f)R^(11f),(CH₂)_(r)NHC(═NR^(11f))NR^(11f)R^(11f), (CH₂)_(r)S(O)_(p)R^(11b),(CH₂)_(r)S(O)₂NR^(11f)R^(11f), (CH₂)_(r)NR^(11f)S(O)₂R^(11b), and(CH₂)_(r)phenyl substituted with 0-3 R^(11e); R^(11d), at eachoccurrence, is independently selected from methyl, CF₃, C₂₋₆ alkylsubstituted with 0-3 R^(11e), C₃₋₆ alkenyl, C₃₋₆ alkynyl, and a C₃₋₁₀carbocyclic residue substituted with 0-3 R^(11c); R^(11e), at eachoccurrence, is independently selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,(CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(11f)R^(11f), and (CH₂)_(r)phenyl, wherein the phenyl on the(CH₂)_(r)phenyl is substituted with 0-5 substituents selected from F,Cl, Br, I, NO₂, C₁₋₆alkyl, OH, and NR^(11f)R^(11f); R^(11f), at eachoccurrence, is independently selected from H, C₁₋₆ alkyl, and C₃₋₆cycloalkyl; R^(11g) is selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,(CH₂)_(r)phenyl, C(O)R^(11f), C(O)OR^(11h), and SO₂R^(11h); R^(11h), ateach occurrence, is independently selected from C₁₋₆ alkyl, and C₃₋₆cycloalkyl; R¹², is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CHR′)_(q)OH, (CH₂)_(q)SH, (CHR′)_(q)OR^(12d),(CH₂)_(q)SR^(12d), (CHR′)_(q)NR^(12a)R^(12a), (CH₂)_(r)C(O)OH,(CH₂)_(r)C(O)R^(12b), (CH₂)_(r)C(O)NR^(12a)R^(12a),(CH₂)_(q)NR^(12a)C(O)R^(12a), (CH₂)_(r)OC(O)NR^(12a)R^(12a),(CH₂)_(r)NR^(12a)C(O)OR^(12b), (CH₂)_(q)NR^(12a)C(O)NHR^(12a),(CH₂)_(r)C(O)OR^(12b), (CH₂)_(q)OC(O)R^(12b), (CH₂)_(q)S(O)_(p)R^(12b),(CH₂)_(q)S(O)₂NR^(12a)R^(12a), (CH₂)_(q)NR^(12a)S(O)₂R^(12b), C₁₋₆haloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5R^(12c), and a (CR′R¹⁷)_(r)-5-10 membered heterocyclic system containing1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^(12c);R^(12a), at each occurrence, is independently selected from H, C₁₋₆alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(12e), and a (CH₂)_(r)-4-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R^(12e); alternatively, two R^(12a)s, along with the N to whichthey are attached, join to form a 5-6 membered heterocyclic systemcontaining 1-2 heteroatoms selected from NR^(12g), O, and S andoptionally fused with a benzene ring or a 6-membered aromaticheterocycle; R^(12b), at each occurrence, is independently selected fromC₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclicresidue substituted with 0-2 R^(12e), and a (CH₂)_(r)-4-6 memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-3 R^(12e); R^(12c), at each occurrence, isindependently selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, (CF₂)_(r)CF₃, NO₂, CN,(CH₂)_(r)NR^(12f)R^(12f), (CH₂)_(r)OH, (CH₂)_(r)OC₁₋₄ alkyl,(CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(12b),(CH₂)_(r)C(O)NR^(12f)R^(12f), (CH₂)_(r)NR^(12f)C(O)R^(12a),(CH₂)_(r)C(O)OC₁₋₄ alkyl, (CH₂)_(r)OC(O)R^(12b),(CH₂)_(r)C(═NR^(12f))NR^(12f)R^(12f),(CH₂)_(r)NHC(═NR^(12f))NR^(12f)R^(12f), (CH₂)_(r)S(O)_(p)R^(12b),(CH₂)_(r)S(O)₂NR^(12f)R^(12f), (CH₂)_(r)NR^(12f)S(O)₂R^(12b), and(CH₂)_(r)phenyl substituted with 0-3 R^(12e); R^(12d), at eachoccurrence, is independently selected from methyl, CF₃, C₂₋₆ alkylsubstituted with 0-3 R^(12e), C₃₋₆ alkenyl, C₃₋₆ alkynyl, and a C₃₋₁₀carbocyclic residue substituted with 0-3 R^(12c); R^(12e), at eachoccurrence, is independently selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,(CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(12f)R^(12f), and (CH₂)_(r)phenyl; R^(12f), at eachoccurrence, is independently selected from H, C₁₋₆ alkyl, and C₃₋₆cycloalkyl; R^(12g) is selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,(CH₂)_(r)phenyl, C(O)R^(12f), C(O)OR^(12h), and SO₂R^(12h); R^(12h), ateach occurrence, is independently selected from C₁₋₆ alkyl, and C₃₋₆cycloalkyl; alternatively, R¹¹ and R¹² join to form a C₃₋₁₀ cycloalkyl,a 5-6-membered lactone or lactam, or a 4-6-membered saturatedheterocycle containing 1-2 heteroatoms selected from O, S, and NR^(11g)and optionally fused with a benzene ring or a 6-membered aromaticheterocycle; R¹³, at each occurrence, is independently selected fromC₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, (CF₂)_(w)CF₃,(CH₂)_(q)NR^(13a)R^(13a), (CHR′)_(q)OH, (CH₂)_(q)OR^(13b), (CH₂)_(q)SH,(CH₂)_(q)SR^(13b), (CH₂)_(w)C(O)OH, (CH₂)_(w)C(O)R^(13b),(CH₂)_(w)C(O)NR^(13a)R^(13a), (CH₂)_(q)NR^(13d)C(O)R^(13a),(CH₂)_(w)C(O)OR^(13b), (CH₂)_(q)OC(O)R^(13b), (CH₂)_(w)S(O)_(p)R^(13b),(CH₂)_(w)S(O)₂NR^(13a)R^(13a), (CH₂)_(q)NR^(13d)S(O)₂R^(13b), and(CH₂)_(w)-phenyl substituted with 0-3 R^(13c); R^(13a), at eachoccurrence, is independently selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and phenyl substituted with 0-3 R^(13c); R^(13b), at eachoccurrence, is independently selected from C₁₋₆ alkyl, C₃₋₆ cycloalkyl,and phenyl substituted with 0-3 R^(13c); R^(13c), at each occurrence, isindependently selected from C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, (CH₂)_(r)OH, (CH₂)_(r)SC₁₋₅alkyl, and (CH₂)_(r)NR^(13d)R^(13d); R^(13d), at each occurrence, isindependently selected from H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; R¹⁴, ateach occurrence, is independently selected from H, C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,(CHR′)_(r)NR^(14a)R^(14a), (CHR′)_(r)OH, (CHR′)_(r)O(CHR′)_(r)R^(14d),(CHR′)_(r)SH, (CHR′)_(r)C(O)H, (CHR′)_(r)S(CHR′)_(r)R^(14d),(CHR′)_(r)C(O)OH, (CHR′)_(r)C(O)(CHR′)_(r)R^(14b),(CHR′)_(r)C(O)NR^(14a)R^(14a), (CHR′)_(r)NR^(14f)C(O)(CHR′)_(r)R^(14b),(CHR′)_(r)OC(O)NR^(14a)R^(14a),(CHR′)_(r)NR^(14f)C(O)O(CHR′)_(r)R^(14b),(CHR′)_(r)C(O)O(CHR′)_(r)R^(14d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(14b),(CHR′)_(r)C(═NR^(14f))NR^(14a)R^(14a),(CHR′)_(r)NHC(═NR^(14f))NR^(14f)R^(14f),(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(14b), (CHR′)_(r)S(O)₂NR^(14a)R^(14a),(CHR′)_(r)NR^(14f)S(O)₂(CHR′)_(r)R^(14b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′,(CHR′)_(r)phenyl substituted with 0-3 R^(14e), and a (CH₂)_(r)-4-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(15e), or two R¹⁴ substituents onadjacent atoms on ring A form to join a 5-6 membered heterocyclic systemcontaining 1-3 heteroatoms selected from N, O, and S substituted with0-2 R^(15e); R^(14a), at each occurrence, is independently selected fromH, C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclicresidue substituted with 0-5 R^(14e), and a (CH₂)_(r)-4-10 memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-2 R^(14e); R^(14b), at each occurrence, isindependently selected from C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a(CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-3 R^(14e), and(CH₂)_(r)-4-6 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-2 R^(14e); R^(14d), ateach occurrence, is independently selected from C₃₋₈ alkenyl, C₃₋₈alkynyl, methyl, CF₃, C₂₋₆ alkyl substituted with 0-3 R^(14e), a(CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(14e), and a(CH₂)_(r)4-6 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(14e); R^(14e), ateach occurrence, is independently selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(14f)R^(14f), and (CH₂)_(r)phenyl; R^(14f), at eachoccurrence, is independently selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and phenyl; R¹⁵, at each occurrence, is independentlyselected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂,CN, (CR′R′)_(r)NR^(15a)R^(15a), (CR′R′)_(r)OH,(CR′R′)_(r)O(CHR′)_(r)R^(15d), (CR′R′)_(r)SH, (CR′R′)_(r)C(O)H,(CR′R′)_(r)S(CHR′)_(r)R^(15d), (CR′R′)_(r)C(O)OH,(CR′R′)_(r)C(O)(CHR′)_(r)R^(15b), (CR′R′)_(r)C(O)NR^(15a)R^(15a),(CR′R′)_(r)NR^(15f)C(O)(CHR′)_(r)R^(15b),(CR′R′)_(r)OC(O)NR^(15a)R^(15a),(CR′R′)_(r)NR^(15f)C(O)O(CHR′)_(r)R^(15b),(CR′R′)_(r)NR^(15f)C(O)NR^(15f)R^(15f),(CR′R′)_(r)C(O)O(CHR′)_(r)R^(15d), (CR′R′)_(r)OC(O)(CHR′)_(r)R^(15b),(CR′R′)_(r)C(═NR^(15f))NR^(15a)R^(15a),(CR′R′)_(r)NHC(═NR^(15f))NR^(15f)R^(15f),(CR′R′)_(r)S(O)_(p)(CHR′)_(r)R^(15b), (CR′R′)_(r)S(O)₂NR^(15a)R^(15a),(CR′R′)_(r)NR^(15f)S(O)₂(CHR′)_(r)R^(15b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′,(CR′R′)_(r)phenyl substituted with 0-3 R^(15e), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(15e); R^(15a), at each occurrence, isindependently selected from H, C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a(CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(15e), and a(CH₂)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-2 R^(15e); alternatively,two R^(15a)s, along with the N to which they are attached, join to forma 5-6 membered heterocyclic system containing 1-2 heteroatoms selectedfrom NR^(15h), O, and S and optionally fused with a benzene ring or a6-membered aromatic heterocycle; R^(15b), at each occurrence, isindependently selected from C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a(CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-3 R^(15e), and(CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-2 R^(15e); R^(15d), ateach occurrence, is independently selected from C₃₋₈ alkenyl, C₃₋₈alkynyl, methyl, CF₃, C₂₋₆ alkyl substituted with 0-3 R^(15e), a(CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(15e), and a(CH₂)_(r)5-6 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(15e); R^(15e), ateach occurrence, is independently selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(15f)R^(15f), (CH₂)_(r)phenyl, and a heterocycle substitutedwith 0-1 R^(15g), wherein the heterocycle is selected from imidazole,thiazole, oxazole, pyrazole, 1,2,4-triazole, 1,2,3-triazole, isoxazole,and tetrazole,; R^(15f), at each occurrence, is independently selectedfrom H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and phenyl; R^(15g) is selectedfrom methyl, ethyl, acetyl, and CF₃; R^(15h) is selected from H, C₁₋₆alkyl, C₃₋₆ cycloalkyl, (CH₂)_(r)phenyl, C(O)R^(15f), C(O)OR^(15i), andSO₂R^(15i); R^(15i), at each occurrence, is independently selected fromC₁₋₆ alkyl, C₃₋₆ cycloalkyl; R¹⁶, at each occurrence, is independentlyselected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆cycloalkyl, Cl, Br, I, F, NO₂, CN, (CHR′)_(r)NR^(16a)R^(16a),(CHR′)_(r)OH, (CHR′)_(r)O(CHR′)_(r)R^(16d), (CHR′)_(r)SH,(CHR′)_(r)C(O)H, (CHR′)_(r)S(CHR′)_(r)R^(16d), (CHR′)_(r)C(O)OH,(CHR′)_(r)C(O)(CHR′)_(r)R^(16b), (CHR′)_(r)C(O)NR^(16a)R^(16a),(CHR′)_(r)NR^(16f)C(O)(CHR′)_(r)R^(16b),(CHR′)_(r)C(O)O(CHR′)_(r)R^(16d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(16b),(CHR′)_(r)C(═NR^(16f))NR^(16a)R^(16a),(CHR′)_(r)NHC(═NR^(16f))NR^(16f)R^(16f),(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(16b), (CHR′)_(r)S(O)₂NR^(16a)R^(16a),(CHR′)_(r)NR^(16f)S(O)₂(CHR′)_(r)R^(16b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′, and(CHR′)_(r)phenyl substituted with 0-3 R^(16e); R^(16a), at eachoccurrence, is independently selected from H, C₁₋₆ alkyl, C₃₋₈ alkenyl,C₃₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5R^(16e), and a (CH₂)_(r)-5-10 membered heterocyclic system containing1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^(16e);R^(16b), at each occurrence, is independently selected from C₁₋₆ alkyl,C₃₋₈ alkenyl, C₃₋₈ alkynyl, a (CH₂)_(r)C₃₋₆ carbocyclic residuesubstituted with 0-3 R^(16e), and a (CH₂)_(r)-5-6 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-2 R^(16e); R^(16d), at each occurrence, is independently selectedfrom C₃₋₈ alkenyl, C₃₋₈ alkynyl, methyl, CF₃, C₂₋₆ alkyl substitutedwith 0-3 R^(16e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with0-3 R^(16e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^(16e);R^(16e), at each occurrence, is independently selected from C₁₋₆ alkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(16f)R^(16f), and (CH₂)_(r)phenyl; R^(16f), at eachoccurrence, is independently selected from H, C₁₋₅ alkyl, and C₃₋₆cycloalkyl, and phenyl; R′, at each occurrence, is independentlyselected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆cycloalkyl, and (CH₂)_(r)phenyl substituted with R^(e); R^(e) isselected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl,OH, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(f)R^(f), and (CH₂)_(r)phenyl;R^(f) is selected from H, C₁₋₅ alkyl, and C₃₋₆ cycloalkyl, and phenyl;R¹⁸, at each occurrence, is independently selected from H, C₁₋₆ alkyl,C₃₋₆ alkenyl, C₃₋₆ alkynyl, C(O)—C₃₋₆ alkyl, C(O)—C₃₋₆ alkenyl,C(O)—C₃₋₆ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and (CH₂)_(r)phenylsubstituted with R^(e); R¹⁹ is absent, taken with the nitrogen to whichit is attached to form an N-oxide, or selected from C₁₋₈ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, (CH₂)_(q)C(O)R^(19b),(CH₂)_(q)C(O)NR^(19a)R^(19a), (CH₂)_(q)C(O)OR^(19b), and a(CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(19c);R^(19a), at each occurrence, is selected from H, C₁₋₆ alkyl,(CH₂)_(r)C₃₋₆ cycloalkyl, and phenyl; R^(19b), at each occurrence, isselected from C₁₋₆ alkyl, C₂₋₈ alkenyl, (CH₂)_(r)C₃₋₆ cycloalkyl, C₂₋₈alkynyl, and phenyl; R^(19c), at each occurrence, is selected from C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, (CH₂)_(r)OH, (CH₂)_(r)SC₁₋₅alkyl, (CH₂)_(r)NR^(19a)R^(19a), and (CH₂)_(r)phenyl; alternatively, R¹⁹joins with R⁷, R⁹, or R¹¹ to form a 5, 6 or 7 membered piperidiniumspirocycle or pyrrolidinium spirocycle substituted with 0-3 R^(a); g isselected from 0, 1, 2, and 3; v is selected from 0, 1, and 2; t isselected from 1 and 2; w is selected from 0 and 1; r is selected from 0,1, 2, 3, 4, and 5; q is selected from 1, 2, 3, 4, and 5; and p isselected from 0, 1, and
 2. 2. The compound of claim 1, wherein: ring Dis selected from

Z is selected from O, S, N(CN), and N(CONH₂); R¹ and R² areindependently selected from H and C₁₋₄ alkyl; R¹⁹ is absent, taken withthe nitrogen to which it is attached to form an N-oxide, or selectedfrom C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and (CH₂)_(r)-phenylsubstituted with 0-3 R^(19c); R^(19c), at each occurrence, is selectedfrom C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br,I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, (CH₂)_(r)OH,(CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(19a)R⁹, and (CH₂)_(r)phenyl;alternatively, R¹⁹ joins with R⁷, R⁹, or R¹¹ to form a 5, 6 or 7membered piperidinium spirocycle or pyrrolidinium spirocycle substitutedwith 0-3 R^(a); R¹³, at each occurrence, is independently selected fromC₁₋₄ alkyl, C₃₋₆ cycloalkyl, (CH₂)NR^(13a)R^(13a), (CHR′)OH,(CH₂)OR^(13b), (CH₂)_(w)C(O)R^(13b), (CH₂)_(w)C(O)NR^(13a)R^(13a),(CH₂)NR^(13d)C(O)R^(13a), (CH₂)_(w)S(O)₂NR^(13a)R^(13a),(CH₂)NR^(13d)S(O)₂R^(13b), and (CH₂)_(w)-phenyl substituted with 0-3R^(13c); R^(13a), at each occurrence, is independently selected from H,C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and phenyl substituted with 0-3 R^(13c);R^(13b), at each occurrence, is independently selected from C₁₋₆ alkyl,C₃₋₆ cycloalkyl, and phenyl substituted with 0-3 R^(13c); R^(13c), ateach occurrence, is independently selected from C₁₋₆ alkyl, C₃₋₆cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl,(CH₂)_(r)OH, and (CH₂)_(r)NR^(13d)R^(13d); R^(13d), at each occurrence,is independently selected from H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; q isselected from 1, 2, and 3; and r is selected from 0, 1, 2, and
 3. 3. Thecompound of claim 2, wherein: E is —(C═O)—(CR⁹R¹⁰)_(v)—(CR¹¹R¹²)—,—(CR⁷R⁸)—(CR⁹R¹⁰)_(v)—(CR¹¹R¹²),

R³ is selected from a (CR^(3a)H)_(r)—C₃₋₈ carbocyclic residuesubstituted with 0-5 R¹⁵, wherein the carbocyclic residue is selectedfrom phenyl, C₃₋₆ cycloalkyl, naphthyl, and adamantyl; and a(CR^(3a)H)_(r)-heterocyclic system substituted with 0-3 R¹⁵, wherein theheterocyclic system is selected from pyridinyl, thiophenyl, furanyl,indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl,benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl,imidazolyl, indolyl, indolinyl, indazolyl, isoindolyl, isothiadiazolyl,isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl,tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, andpyrimidinyl; and R⁵ is selected from (CR^(5a)H)_(t)-phenyl substitutedwith 0-5 R¹⁶; and a (CR^(5a)H)_(t)-heterocyclic system substituted with0-3 R¹⁶, wherein the heterocyclic system is selected from pyridinyl,thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl,benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl,isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl,isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl,1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl,pyrazinyl, and pyrimidinyl.
 4. The compound of claim 3, wherein B isNR¹⁷,

R¹ and R² are H; R¹⁶, at each occurrence, is independently selected fromC₁₋₈ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, CF₃, Cl, Br, I, F,(CH₂)_(r)NR^(16a)R^(16a), NO₂, CN, OH, (CH₂)_(r)OR^(16d),(CH₂)_(r)C(O)R^(16b), (CH₂)_(r)C(O)NR^(16a)R^(16a),(CH₂)_(r)NR^(16f)C(O)R^(16b), (CH₂)_(r)S(O)_(p)R^(16b),(CH₂)_(r)S(O)₂NR^(16a)R^(16a), (CH₂)_(r)NR^(16f)S(O)₂R^(16b), and(CH₂)_(r)phenyl substituted with 0-3 R^(16e); R^(16a), at eachoccurrence, is independently selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3 R^(16e); R^(16b),at each occurrence, is independently selected from C₁₋₆ alkyl, C₃₋₆cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3 R^(16e); R^(16d),at each occurrence, is independently selected from C₁₋₆ alkyl andphenyl; R^(16e), at each occurrence, is independently selected from C₁₋₆alkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅alkyl; and R^(16f), at each occurrence, is independently selected fromH, and C₁₋₅ alkyl.
 5. The compound of claim 4, wherein E is—(CR⁷R⁸)—(CR⁹R¹⁰)_(n)—(CR¹¹R¹²); B is NR¹⁷; R⁵ is CH₂phenyl substitutedwith 0-3 R¹⁶; and r is selected from 0, 1, and
 2. 6. The compound ofclaim 5, wherein: Z is selected from O, N(CN) and NC(O)NH₂; and R⁴ isselected from H and R⁵.
 7. The compound of claim 6, wherein: R³ is aC₃₋₁₀ carbocyclic residue substituted with 0-3 R¹⁵, wherein thecarbocyclic residue is selected from cyclopropyl, cyclopentyl,cyclohexyl, phenyl, naphthyl and adamantyl, and a(CR^(3a)H)_(r)-heterocyclic system substituted with 0-3 R¹⁵, wherein theheterocyclic system is selected from pyridinyl, thiophenyl, furanyl,indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl,benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl,imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl,piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl,thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; and R¹⁵,at each occurrence, is independently selected from C₁₋₈ alkyl,(CH₂)_(r)C₃₋₆ cycloalkyl, CF₃, Cl, Br, I, F, (CH₂)_(r)NR^(15a)R^(15a),NO₂, CN, OH, (CH₂)_(r)OR^(15d), (CH₂)_(r)C(O)R^(15b),(CH₂)_(r)C(O)NR^(15a)R^(15a), (CH₂)_(r)NR^(15f)C(O)R^(15b),(CH₂)_(r)OC(O)NR^(15a)R^(15a), (CH₂)_(r)NR^(15f)C(O)OR^(15b),(CH₂)_(r)S(O)_(p)R^(15b), (CH₂)_(r)S(O)₂NR^(15a)R^(15a),(CH₂)_(r)NR^(15f)S(O)₂R^(15b), (CH₂)_(r)phenyl substituted with 0-3R^(15e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-2 R^(15e);R^(15a), at each occurrence, is independently selected from H, C₁₋₆alkyl, C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3R^(15e); alternatively, two R^(15a)s, along with the N to which they areattached, join to form a 5-6 membered heterocyclic system containing 1-2heteroatoms selected from NR^(15g), O, and S and optionally fused with abenzene ring or a 6-membered aromatic heterocycle; R^(15b), at eachoccurrence, is independently selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3 R^(15e); R^(15d),at each occurrence, is independently selected from C₁₋₆ alkyl andphenyl; R^(15e), at each occurrence, is independently selected from C₁₋₆alkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅alkyl; and R^(15f), at each occurrence, is independently selected fromH, and C₁₋₅ alkyl.
 8. The compound of claim 4, wherein: Z is O, N(CN),and NC(O)NH₂;

B is NR¹⁷; R⁵ is CH₂phenyl substituted with 0-3 R¹⁶; and r is selectedfrom 0, 1, and
 2. 9. The compound of claim 8, wherein: Z is selectedfrom O, N(CN) and NC(O)NH₂; R³ is a C₃₋₁₀ carbocyclic residuesubstituted with 0-3 R¹⁵, wherein the carbocyclic residue is selectedfrom cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyland adamantyl, and a (CR^(3a)H)_(r)-heterocyclic system substituted with0-3 R¹⁵, wherein the heterocyclic system is selected from pyridinyl,thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl,benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl,isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl,isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl,1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl,pyrazinyl, and pyrimidinyl; R¹⁵, at each occurrence, is independentlyselected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, CF₃, Cl, Br, I, F,(CH₂)_(r)NR^(15a)R^(15a), NO₂, CN, OH, (CH₂)_(r)OR^(15d),(CH₂)_(r)C(O)R^(15b), (CH₂)_(r)C(O)NR^(15a)R^(15a),(CH₂)_(r)NR^(15f)C(O)R^(15b), (CH₂)_(r)OC(O)NR^(15a)R^(15a),(CH₂)_(r)NR^(15f)C(O)OR^(15b), (CH₂)_(r)S(O)_(p)R^(15b),(CH₂)_(r)S(O)₂NR^(15a)R^(15a), (CH₂)_(r)NR^(15f)S(O)₂R^(15b),(CH₂)_(r)phenyl substituted with 0-3 R^(15e), and a (CH₂)_(r)-5-6membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(15e); R^(15a), at each occurrence, isindependently selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and(CH₂)_(r)phenyl substituted with 0-3 R^(15e); alternatively, twoR^(15a)s, along with the N to which they are attached, join to form a5-6 membered heterocyclic system containing 1-2 heteroatoms selectedfrom NR^(15g), O, and S and optionally fused with a benzene ring or a6-membered aromatic heterocycle; R^(15b), at each occurrence, isindependently selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and(CH₂)_(r)phenyl substituted with 0-3 R^(15e); R^(15d), at eachoccurrence, is independently selected from C₁₋₆ alkyl and phenyl;R^(15e), at each occurrence, is independently selected from C₁₋₆ alkyl,Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅ alkyl; andR^(15f), at each occurrence, is independently selected from H, and C₁₋₅alkyl.
 10. The compound of claim 9, wherein:

A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, andphenyl.
 11. The compound of claim 3, wherein: E is selected from(C═O)—(CR⁹R¹⁰)_(v)—(CR¹¹R¹²)—,

R³ is a C₃₋₁₀ carbocyclic residue substituted with 0-3 R¹⁵, wherein thecarbocyclic residue is selected from cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, phenyl, naphthyl and adamantyl, and a(CR^(3a)H)_(r)-heterocyclic system substituted with 0-3 R¹⁵, wherein theheterocyclic system is selected from pyridinyl, thiophenyl, furanyl,indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl,benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl,imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl,piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl,thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl.
 12. Thecompound of claim 11, wherein: E is (C═O)—(CR⁹R¹⁰)_(v)—(CR¹¹R¹²)—. 13.The compound of claim 11, wherein: E is

A is selected from cyclopropyl, cyclobutyl, cyclopentyl cyclohexyl, andphenyl.
 14. The compound of claim 4, wherein: R⁹, is selected from H,C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, F, Cl, Br, I, NO₂, CN,(CHR′)_(r)OH, (CH₂)_(r)OR^(9d), (CH₂)_(r)SR^(9d),(CH₂)_(r)NR^(9a)R^(9a), (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(9b),(CH₂)_(r)C(O)NR^(9a)R^(9a), (CH₂)_(r)NR^(9a)C(O)R^(9b),(CH₂)_(r)NR^(9a)C(O)H, C₁₋₆ haloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclicresidue substituted with 0-5 R^(9c), and a (CH₂)_(r)-5-10 memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-3 R^(9c); R^(9a), at each occurrence, isindependently selected from H, C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a(CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(9e), and a(CH₂)_(r)-4-10 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(9e); alternatively,two R^(9a)s, along with the N to which they are attached, join to form a5-6 membered heterocyclic, system containing 1-2 heteroatoms selectedfrom NR^(9g), O, and S and optionally fused with a benzene ring or a6-membered aromatic heterocycle; R¹⁰, is selected from H, C₁₋₆ alkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, F, Cl, Br, I, NO₂, CN, (CHR′)_(r)OH,(CH₂)_(r)OR^(10d), (CH₂)_(r)SR^(10d), (CH₂)_(r)NR^(10a)R^(10a);alternatively, R⁹ and R¹⁰ join to form ═O, a C₃₋₁₀ cycloalkyl, a5-6-membered lactone or lactam, or a 4-6-membered saturated heterocyclecontaining 1-2 heteroatoms selected from O, S, and NR^(10g) andoptionally fused with a benzene ring or a 6-membered aromaticheterocycle; R¹¹, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CR′R¹⁷)_(q)OH, (CH₂)_(q)SH, (CR′R¹⁷)_(q)OR^(11d),(CH₂)_(q)SR^(11d); R¹², is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CHR′)_(q)OH, (CH₂)_(q)SH, (CHR′)_(q)OR^(12d),(CH₂)_(q)SR^(12d), (CHR′)_(q)NR^(12a)R^(12a); and R¹⁴, at eachoccurrence, is independently selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,(CHR′)_(r)NR^(14a)R^(14a), (CHR′)_(r)OH, (CHR′)_(r)O(CHR′)_(r)R^(14d),(CHR′)_(r)SH, (CHR′)_(r)C(O)H, (CHR′)_(r)S(CHR′)_(r)R^(14d).
 15. Thecompound of claim 1 wherein the compound is selected from:N-(3-Acetyl-phenyl)-N′-{-3-[(2S)-3-benzyl]-5-oxo-piperazin-1-yl-propyl}-urea;N-(5-Acetyl-4-methyl-thiazol-2-yl)-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-(5-Acetyl-4-methyl-thiazol-2-yl)-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-3,6-dioxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-(5-Acetyl-4-methyl-thiazol-2-yl)-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-(2S)-2-hydroxymethyl-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-(5-Acetyl-4-methyl-thiazol-2-yl)-N′{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl-(2R)-2-hydroxymethyl-3-oxo-piperizine-2-yl-methyl)-cyclohexyl}-urea;N-(5-Acetyl-4-methyl-thiazol-2-yl)-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-3-oxo-4-N-methyl-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-(5-Acetyl-4-methyl-thiazol-2-yl)-N′-{(1R,2S)-2-[(5S)-5-(3-fluoro-benzyl)-3-oxo-4-N-methyl-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-(5-Acetyl-4-methyl-thiazol-2-yl)-N′-{(1R,2S)-2-[(5S)-5-(2-fluoro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-(5-Acetyl-4-methyl-thiazol-2-yl)-N′-{(1R,2S)-2-[(5S)-5-benzyl-3,6-di-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-(5-Acetyl-4-methyl-thiazol-2-yl)-N′-{(1R,2S)-2-[(5S)-5-benzyl-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-(5-Acetyl-4-methyl-thiazol-2-yl)-N′-{(1R,2S)-2-[(5R)-5-(4-fluoro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-(5-Acetyl-4-methyl-thiazol-2-yl)-N′-{(1R,2S)-2-[(5S)-5-(4-chloro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-(5-Acetyl-4-methyl-thiazol-2-yl)-N′-{(1R,2S)-2-[(5R)-5-(4-chloro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-(5-Acetyl-4-methyl-thiazol-2-yl)-N′-{(1R,2S)-2-[(5S)-5-(1-phenyl-ethyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-(5-Acetyl-4-methyl-thiazol-2-yl)-N′-{(1R,2S)-2-[3-oxo-4-N-(4-fluoro-benzyl)-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-phenyl-N′-{(1R,2S)-2-[(5S)-5-benzyl-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-phenyl-N′-{(1R,2S)-2-[(5R)-5-benzyl-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-phenyl-N′-{(1R,2S)-2-[(5S)-5-benzyl-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-cyanoguanidine;N-phenyl-N′-{(1R,2S)-2-[3-oxo-4-N-(4-fluoro-benzyl)-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-phenyl-N′-{(1R,2S)-2-[(2S)-2-benzyl-6-oxo-morpholin-4-yl-methyl]-cyclohexyl}-urea;N-(3-cyanophenyl)-N′-{(1R,2S)-2-[(5S)-5-benzyl-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-(3-cyanophenyl)-N′-{(1R,2S)-2-[(5S)-5-benzyl-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-cyanoguanidine;N-(3-Acetyl-4-fluorophenyl)-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-(3-acetylphenyl)-N′-{(1R,2S)-2-[(5S)-5-benzyl-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-cyanoguanidine;N-(3-acetylphenyl)-N′-{(1R,2S)-2-[(5S)-5-benzyl-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-(3-acetylphenyl)-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-(3-acetylphenyl)-N′-{(1R,2S)-2-[(5S)-5-(3-fluoro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-(3-acetylphenyl)-N′-{(1R,2S)-2-[(5S)-(2-fluoro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-(3-acetylphenyl)-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-(2S)-2-hydroxymethyl-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-(3-acetylphenyl)-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-(2R)-2-hydroxymethyl-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-(3-Acetyl-phenyl)-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-3-oxo-4-N-methyl-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-(3-Acetyl-phenyl)-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-3-oxo-4-N-benzyl-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-(3-Acetyl-phenyl)-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-3,6-di-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-(3-Acetyl-phenyl)-N′-{(1R,2S)-2-[(5R)-5-(4-fluoro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-(3-Acetyl-phenyl)-N′-{(1R,2S)-2-[(5S)-5-(4-chloro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-(3-Acetyl-phenyl)-N′-{(1R,2S)-2-[(5S)-5-(3-cyano-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-(3-Acetyl-phenyl)-N′-{(1R,2S)-2-[(5R)-5-(3-cyano-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-(3-Acetyl-phenyl)-N′-{(1R,2S)-2-[(5S)-5-(1-phenyl-ethyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-(3-Acetyl-phenyl)-N′-{(1R,2S)-2-[3-oxo-4-N-(4-fluoro-benzyl)-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-(3-Acetyl-phenyl)-N′-{(1R,2S)-2-[(2S)-2-(benzyl)-6-oxo-morpholin-4-yl-methyl]-cyclohexyl}-urea;N-(3-Acetyl-phenyl)-N′-{(1R,2S)-2-[4-oxo-1,3,4,6,11,11a-hexahydro-pyrazino[1.2-b]-isoquinolin-2-yl-methyl]-cyclohexyl}-urea;N-[3-(1-hydroxy-ethyl)-phenyl]-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-(2S)-(2-hydroxy-methyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-(indazol-5-yl)-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-3,6-di-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-(indazol-5-yl)-N′-{(1R,2S)-2-[(5S)-5-benzyl-3,6-di-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-(indazol-5-yl)-N′-{(1R,2S)-2-[(5S)-5-benzyl-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-(indazol-5-yl)-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-(3,5-di-Acetyl-phenyl)-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-(3,5-di-Acetyl-phenyl)-N′-{(1R,2S)-2-[(5S)-5-(3-fluoro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-(3,5-di-Acetyl-phenyl)-N′-{(1R,2S)-2-[(5S)-5-(2-fluoro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-(3,5-di-Acetyl-phenyl)-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-3-oxo-4-N-methyl-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-(3,5-di-Acetyl-phenyl)-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-3,6-di-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-(3,5-di-Acetyl-phenyl)-N′-{(1R,2S)-2-[(5R)-5-(4-fluoro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-(3,5-di-Acetyl-phenyl)-N′-{(1R,2S)-2-[(5S)-5-(1-phenyl-ethyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-(3,5-di-Acetyl-phenyl)-N′-{(1R,2S)-2-[(2S)-2-(benzyl)-6-oxo-morpholin-4-yl-methyl]-cyclohexyl}-urea;N-(3,5-di-Acetyl-phenyl)-N′-{(1R,2S)-2-[(5S)-5-(2-fluoro-benzyl)-3,6-di-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-(3,5-di-Acetyl-phenyl)-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-3-oxo-4-N-methyl-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-(3,5-di-Acetyl-phenyl)-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-3-oxo-4-N-benzyl-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-N′-{(1R,2S)-2-[(5S)-5-(2-fluoro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-(2S)-2-hydroxymethyl-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-(2R)-2-hydroxymethyl-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-3-oxo-4-N-methyl-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-3-oxo-4-N-benzyl-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-N′-{(1R,2S)-2-[(5R)-5-(4-fluoro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-N′-{(1R,2S)-2-[(5S)-5-(4-chloro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-N′-{(1R,2S)-2-[(5S)-5-(3-cyano-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-N′-{(1R,2S)-2-[(5R)-5-(3-cyano-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-N′-{(1R,2S)-2-[(5S)-5-(1-phenyl-ethyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-N′-{(1R,2S)-2-[3-oxo-4-N-(4-fluoro-benzyl)-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-N′-{(1R,2S)-2-[(2S)-2-(benzyl)-6-oxo-morpholin-4-yl-methyl]-cyclohexyl}-urea;N-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-)-N′-{(1R,2S)-2-[4-oxo-1,3,4,6,11,11a-hexahydro-pyrazino[1.2-b]-isoquinolin-2-yl-methyl]-cyclohexyl}-urea;N-[indolin-5-yl)phenyl]-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-[indolin-5-yl)phenyl]-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-(4-methyl-thiazol-2-yl)-N′-{(1R,2S)-2-[(5S)-5-(3-fluoro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-(thiadiazol-2-yl)-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;N-(1-methyl-pyrazol-3-yl)-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea;andN-(thiazol-2-yl)-N′-{(1R,2S)-2-[(5S)-5-(4-fluoro-benzyl)-3-oxo-piperazin-1-yl-methyl]-cyclohexyl}-urea.16. A pharmaceutical composition, comprising a pharmaceuticallyacceptable carrier and a therapeutically effective amount of a compoundaccording to claim
 1. 17. A method for inhibiting CCR3 receptor activitycomprising administering to a patient in need thereof a therapeuticallyeffective amount of a compound according to claim
 1. 18. A method fortreating asthma, comprising administering to a patient in need thereof atherapeutically effective amount of a compound according to claim
 1. 19.A pharmaceutical composition comprising a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound accordingto claim 7, or a pharmaceutically acceptable salt thereof.
 20. Themethod of claim 17 wherein inhibiting of CCR3 receptor activitycomprises contacting a CCR3 receptor with an effective inhibitory amountof the compound.
 21. A method for treating inflammatory disorders whichare at least partially mediated by CCR3 comprising administering to apatient in need thereof a therapeutically effective amount of a compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof. 22.A method according to claim 21, wherein the disorder is selected fromasthma, allergic rhinitis, atopic dermatitis, inflammatory boweldiseases, idiopathic pulmonary fibrosis, bullous pemphigoid, allergiccolitis, eczema, conjunctivitis, familial eosinophilia, eosinophiliccellulitis, eosinophilic pneumonias, eosinophilic fasciitis,eosinophilic gastroenteritis, and drug induced eosinophilia.
 23. Themethod according to claim 22, wherein the disorder is selected fromasthma, allergic rhinitis, atopic dermatitis, and inflammatory boweldiseases.
 24. The method according to claim 23, wherein the disorder isasthma.
 25. A method for treating asthma, comprising administering to apatient in need thereof a therapeutically effective amount of a compoundaccording to claim
 7. 26. A pharmaceutical composition comprising apharmaceutically acceptable carrier and a therapeutically effectiveamount of a compound according to claim 10, or a pharmaceuticallyacceptable salt thereof.
 27. A method for treating asthma, comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound according to claim 10.